CN103585632A - Application of bile acid chelating agent or/and vitamin D in preparing drug for preventing and treating non-alcoholic fatty liver disease - Google Patents
Application of bile acid chelating agent or/and vitamin D in preparing drug for preventing and treating non-alcoholic fatty liver disease Download PDFInfo
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Abstract
The invention belongs to the technical field of pharmaceutical preparation application, in particular to an application of a bile acid chelating agent or/and vitamin D in preparing a drug for preventing and treating a non-alcoholic fatty liver disease. The bile acid chelating agent is polyamine cation exchange resin and comprises cholestyramine, colestipol and the like, and the vitamin D is selected from vitamin D2, vitamin D3, bioactive vitamin D3 and a derivative of the bioactive vitamin D3. The chelating agent and the vitamin D can be medicated either independently or together. The chelating agent and the vitamin D are combined with intestinal bile acid to reduce fat emulsification, absorption of lipid from diets, and deposition of the lipid in a liver. After the chelating agent and the vitamin D are combined with the intestinal bile acid, liver bile acid synthesis is increased, so that endogenous fatty acid synthesis is inhibited. In addition, the active vitamin D and the derivative thereof also can inhibit inflammation, promotes intestinal reabsorption of the bile acid, inhibits the endogenous fatty acid synthesis, and therefore relieves the non-alcoholic fatty liver disease.
Description
Technical field
The invention belongs to pharmaceutical preparation applied technical field, be specifically related to bile acid chelating agent or/and the application of vitamin D in preparation prevention and treatment non-alcohol fatty liver medicine.
Background technology
1, non-alcohol fatty liver and pathogenesis
Non-alcohol fatty liver comprises a series of diseases, from simple lipid abnormal deposition (simple fat becomes) in liver, to fat, become and with inflammation, become non-alcoholic stellato-hepatitis (non-alcoholic steatohepatitis simultaneously, NASH) liver cirrhosis even, produce hepatocarcinogenesis, patient's history of not indulging in excessive drinking.The concept of non-alcoholic stellato-hepatitis (NASH) is proposed in 1980 by people such as Ludwig the earliest, finds at that time that the performance of alcoholic hepatitis appearred being similar in some patient's hepatic pathologies that there is no heavy drinking history (being less than weekly 40 g ethanol).
Fatty liver and non-alcoholic stellato-hepatitis can comprise that child falls ill at each age group.In the U.S., there is the population of 10-20% to suffer from fatty liver, there is the people of 3-5% to suffer from non-alcoholic stellato-hepatitis.According to estimates, in the relatively advanced city of China, the sickness rate of non-alcohol fatty liver has turned over 2 times in nearly 20 years.Fatty liver or simple fat become at crowd's sickness rate at 10-15%, in overweight people up to 70-80%.Non-alcohol fatty liver, at general population's sickness rate approximately 3%, can reach 15-20% overweight people.
Non-alcoholic stellato-hepatitis is one of typical case's performance of metabolism syndrome.The feature of metabolism syndrome is central obesity, insulin resistant, hypertension, hyperglycemia, hypertriglyceridemia and fatty liver.Triglyceride is the basic feature of non-alcohol fatty liver hepatocellular gathering.Can be by unbalance the causing of picked-up, generation, transhipment or oxidative metabolism of fatty acid.The mechanism of non-alcohol fatty liver liver fat excessive buildup is still not clear.A high-quality research, application cold labeling fatty acid shows, in the liver of patients with nonalcoholic fatty liver disease 60%, triglyceride derives from unsaturated fatty acid in diet, it is synthetic that approximately 26% triglyceride derives from endogenous fatty acid, and it may be too much the main reason of non-alcohol fatty liver morbidity that prompting triglyceride is taken in.
Simple fat becomes, and with hepatocyte triglyceride, gathers, and is considered to the initial stage performance of fatty liver and is reversible.About the evolution mechanism from non-alcoholic fatty liver disease to non-alcoholic stellato-hepatitis, comparatively popular is " two-hit " theory.First strike refers to that lipid material is in hepatocellular abnormal accumulation.Wherein insulin resistant is considered to one of key factor causing the change of hepatocyte fat.The toxic action that blood glucose is too high, has but caused gathering of hepatocyte triglyceride to form fatty liver on the other hand." first strike " increased the susceptibility of liver to " second strike ", causes even cancer of hepatocyte injury, inflammation, fibrosis." second strike " comprises lipid peroxidation, inflammatory factor effect, Adipocyte Factor and mitochondrial oxidation obstacle etc. pathological process.Recently by Research of Animal Model for Study, show, vitamin D deficiency can weight fat liver, becomes fat hepatitis.But how using vitamin D as preparation treatment or the medicine of prevention fatty liver, using how mode and dosage but to have no relevant report as the medicine as preparation treatment or prevention fatty liver.Non-alcohol fatty liver can be divided into four-stage (comprehensively passing judgment on according to aspects such as inflammation, ballooning degeneration of liver cells and fibrosiss in fat change, lobule) according to pathological characteristic, and non-alcoholic stellato-hepatitis is defined as the inflammatory stage of non-alcohol fatty liver.
2. the diagnosis of non-alcohol fatty liver and non-alcoholic stellato-hepatitis
The diagnosis of non-alcohol fatty liver and non-alcoholic stellato-hepatitis remains a challenging job so far.Non-alcohol fatty liver may be followed the rising of serum transaminase and triglyceride, normal but fatty liver still may show as transaminase when even the fatty liver in later stage is correlated with hepatic fibrosis.One studies show that 51 normal patients with nonalcoholic fatty liver diseases of Serum ALT, wherein has 12 with serious bridging fibrosis, and 6 is liver cirrhosis patient.Clinical conventional imaging examination comprises that ultrasonic, CT, MRI etc. are not the goldstandards of diagnosis non-alcohol fatty liver.Ultrasonic lower liver Echoenhance companion decay is the performance of fatty liver, but sensitivity and specificity are all inadequate.At present three kinds of conventional Imaging Methods (ultrasonic, CT and MRI) all can not be distinguished the different phase of non-alcohol fatty liver.Liver biopsy pathologic finding is the current unique method that can make a definite diagnosis non-alcohol fatty liver, can distinguish simple fatty liver and non-alcoholic stellato-hepatitis, not only can understand the order of severity of disease, and can predict prognosis.But, do not have guide suggestion to instruct when who should carry out liver biopsy.
3. the treatment of non-alcohol fatty liver and non-alcoholic stellato-hepatitis
At present, non-alcohol fatty liver and non-alcoholic stellato-hepatitis do not have the recognized standard therapeutic scheme.The most important condition for the treatment of non-alcohol fatty liver and non-alcoholic stellato-hepatitis is to change lifestyles, and strengthens taking exercise, avoiding drinking, lose weight, and balanced nutrients and meals.Although curative effect is not very sure, still have mechanism to apply some antidotes as protected hepatocyte medicine etc.More promising medicine comprises antioxidant, euglycemic agent (as metformin and Thiazolidinediones etc.) hepatoprotective and lipid lowerers.Yet the application of these medicines remains in dispute, need more research to go to confirm its effect and safety.Need to develop the prevention of new safety and/or reverse the method that fat gathers at liver.
4. bile acid and liver sausage circulation
Bile acid be by cholesterol at the synthetic amphiphatic molecule of liver, cholate can dissolve and digest lipid material.After having meal, bile acid is secreted into duodenum from gallbladder.After emulsification, approximately 95% primary and secondary bile acid heavily absorbs through portal vein and gets back to liver at ileum, and this process is known as " enterohepatic circulation of bile acid ".
The main approach of bile acid biosynthesis is also known as classical pathway and completes under liver cholesterol 7 hydroxylases (CYP7A1) effect.CYP7A1 is one of cytochrome P450 family member.The expression of CYP7A1 and bile acid synthetic is subject to the inhibition of transcriptional level of the little heterodimer (SHP) of negative feedback inhibition and bile acid mediation.SHP suppresses multiple transcription factor and comprises liver X receptor (LXR), liver receptor homologue-1(LRH-1) regulating liver-QI nuclear receptor 4-α (HNF-4alpha), these transcription factor all with the important relationship of having transcribed of CYP7A1.
In addition, bile acid self also can stimulate small intestine cells to be expressed as fibroblast growth factor 15(FGF15, mankind FGF19 homologue) express, FGF15 is combined with its receptor FGFR4 to liver and is suppressed CYP7A1 expression through blood circulation, thereby suppress liver bile acid, generates.At present, about SHP, to what extent participate in FGF15/19 signal path the inhibitory action of CYP7A1 is also existed to dispute.
The synthetic elementary bile acid main component of human liver is chenodeoxy cholic acid (accounting for 45%) and cholic acid (accounting for 31%).Elementary bile acid after synthetic is combined into conjugated bile acid at liver and aminoacid (being mainly glycine and taurine).On the feed with the stimulation of cholecystokinin under, bile acid discharges and secretes to duodenum from gallbladder, participates in digestion and absorption that emulsification promotes lipid material in diet.By liver sausage, circulate, approximately have 95% bile acid heavily to be absorbed through portal vein and get back to liver at ileum, under the effect of intestinal microbial population, part bile acid goes hydroxylating to generate lithocholic acid and deoxycholic acid, is called as " secondary bile acid ".
The biologic activity of bile acid is regulated and controled by many factors.First, bile acid is chenodeoxy cholic acid and cholic acid especially, can suppress liver bile acid biosynthesis.Elementary bile acid can activate its nuclear receptor as part and comprise method Buddhist nun ester X receptor (FXR) and then be combined with specific cis-acting elements and then induce little heterodimer (SHP) gene expression, and SHP suppresses the expression that series of genes comprises bile acid biosynthesis key enzyme CYP7A1.
In addition, activate the expression that FXR can also regulate lipid metabolism related gene (as SREBP-1c).The growing amount of liver tg depends primarily on fatty acid synthesis rate, the synthetic control of fatty acid of the regulation and control such as the synthetic fatty acid beta oxidation activity being regulated and controled by PPAR α (NR1C1) to a great extent of fatty acid and SREBP-1c.
Bile acid and FXR all play an important role in the metabolic process of triglyceride and glucose.Before the effect that bile acid reduces triglyceride is found to be in 30 years for the first time, giving hyperlipidemia patient takes chenodeoxy cholic acid and can reduce blood fat.In zoopery, evidence show that bile acid can reduce plasma triglyceride level as cholic acid, at liver, by FXR, induce SHP can suppress SREBP-1c and other lipeses as expression such as FAS and SCD1.
Except FXR, other class nuclear receptors can be identified by lithocholic acid and some cholic acid precursors as Pregnane X Receptor (PXR).The stable effect of transcribing a kind of collaborative stimulating factor PGC-1 α of dependence (PPAR γ co-activator-1 α) of CYP7A1.Yet under physiological status, Hepatocyte nuclear factor 4 α (HNF-4 α) can compete in conjunction with PGC-1 α with PXR, thereby reduces transcribing of CYP7A1.Bile acid activates FXR can also suppress some other important bile acid biosynthesis related gene expression such as SREBP-1c, sterol 12 α-hydroxylase (CYP8B1) and solute carrier family 10 member 1(sodium/bile acid transport protein families, SLC10A1).SLC10A1 is the common transporter of sodium/taurine, participates in liver bile acid from the picked-up of sinusoid/basement membrane.Therefore, the bile acid transport body expression inhibiting of bile acid mediation can cause that the picked-up of liver bile acid reduces the toxicity of the too much bile acid of protection to liver.
5. bile acid chelating agent
Bile acid chelating agent is the resin anion (R.A.) at gastrointestinal tract chelating bile acid.Bile acid chelating agent has had in reducing blood fat the time that surpasses 40 years in clinical practice.In the clinical cohort study of a coronary heart disease primary prevention, have 3806 asymptomatic middle-aged male patients with primary hypercholesterolemia, result demonstration, long-term taking cholestyramine person's T-CHOL and low density lipoprotein, LDL reduce respectively 13% and 20%, and placebo group is respectively 5% and 8%.In addition, in cholestyramine queue, coronary heart attack has reduced.Also have a similar research queue to comprise 370 primary hypercholesterolemia patients, research terminal comprises the variation of specific blood fat and lipoprotein, and it is primarily to study terminal that low density lipoprotein, LDL reduces.Totally 8 weeks gram every day of oral colestipol 2-8, no matter be that granule or tablet can reduce slightly raise patient's low-density lipoprotein white level of low density lipoprotein, LDL.And studies show that colestipol treatment toleration is good, there is no the severe complication report that obvious medicine is relevant.
Although bile acid chelating agent reduces the precise mechanism of blood fat, be still not clear, thereby be commonly referred to be owing to removing a part of intestinal bile acid minimizing bile acid absorption, adjusted enterohepatic circulation of bile acid.Meanwhile, although bile acid chelating agent may be used to other purposes, be conventionally still grouped into pravastatin.Be applied to now treat the three kinds of bile acid chelating agents that have of hypercholesterolemia: cholestyramine, colestipol, and colesevelam.Mechanism is that application bile acid chelating agent can cause liver bile acid biosynthesis to increase, thereby cholesterol consumption increases, and reaches the effect that reduces cholesterol.Bile acid chelating agent can also reduce type 2 diabetes mellitus patient blood sugar level.Bile acid chelating agent is not absorbed direct discharge, so application security is good.Recent research result shows that bile acid chelating agent can improve type 2 diabetes mellitus patient's impaired glucose tolerance.
Yet, apply at present bile acid chelating agent as preparation treatment or prevent the medicine of non-alcohol fatty liver to there is not yet report.
6. non-alcohol fatty liver and vitamin D deficiency
What vitamin D was different with other vitamin is can be synthetic by body self.Under ultraviolet radiation, in skin, cholesterol changes into precursor of vitamine D 3 under the dehydrogenase effect of cholesterol-7.Through self isomerized D3 precursor, under the effect of hepatocyte CYP27A1 or CYP2R1, carry out 25 hydroxylatings, generate the vitamin D3 of activity form after then carrying out 1 hydroxylating under kidney CYP27B1 effect, 1,25(OH)
2d3 is calcitriol (calcitriol).Activity of vitamin d3 is brought into play its life by its nuclear receptor VDR and is learned function, promotes or suppress the expression of target gene.
It has been generally acknowledged that serum 25(OH) D3 level is to represent that vitamin level is normal at 30-50ng/ml.Vitamin D deficiency is defined as serum 25(OH at present) D3 level is lower than 20ng/ml, serum 25(OH) D3 level is defined as vitamin d insufficiency at 20-30ng/ml.The about 5-30% of incidence rate of adult's vitamin D deficiency.In non-cholestatic liver disease patient, vitamin d insufficiency is very general and relevant to disease severity.One studies show that 92% chronic hepatitis patients vitamin D deficiency, wherein has 1/3rd famines.
Non-alcohol fatty liver is closely related with obesity, metabolism syndrome, insulin resistant and type 2 diabetes mellitus, and these diseases or state are all relevant with vitamin D deficiency or deficiency.Studies have found that serum 25(OH) D3 level and Body Mass Index (BMI), body fat content, hypertension, insulin resistant and metabolism syndrome be negative correlation.A clinical cohort study result demonstration about obese adolescents, body fat content and vitamin D deficiency or deficiency have significant correlation.Another studies show that the expression of VDR and the pathology order of severity of non-alcoholic stellato-hepatitis and chronic hepatitis C are negative correlation.
7. the effect of vitamin D in bile acid regulates
On molecular level, bile acid regulates bile acid self anabolism by the negative feedback of FXR and RXR.Vitamin D has played important function in bile acid biosynthesis, secretion and metabolism.For example, research discovery vitamin D can promote intestinal FGF15 to express, thereby and then promotes liver small difference dimer SHP expression to suppress hepatic CYP7A1 expression.Therefore, we infer that vitamin D deficiency may cause bile acid negative feedback regulating action to weaken, thereby non-alcohol fatty liver and non-alcoholic stellato-hepatitis increased the weight of to have played partial action.In addition, vitamin D can promote that the key enzyme CYP3A4(mice of bile acid biosynthesis is CYP3A11) expression regulate bile acid biosynthesis.
Up to now, the pathogenesis of non-alcohol fatty liver is still not clear.The demonstration of epidemiology result, motionless life style, mistake fattiness and the carbohydrate of the morbidity of non-alcohol fatty liver and sitting taken in closely related.Triglyceride excessive buildup is the basic expressions of liver cell fatty degeneration in hepatocyte, may be caused by multiple pathophysiological process, comprising that endogenous fatty acid generates increases, takes in the reasons such as excess fat acid and triglyceride in hyperglycemia that insulin resistant causes and diet.Therefore, optimal scheme is to suppress as far as possible endogenous triglyceride to synthesize, the absorption of can simultaneously cut down one's diet again middle triglyceride and fatty acid.And in the present invention, apply bile acid chelating agent or/and vitamin D, as the medicine of preparation control non-alcohol fatty liver, just can be realized the effect of this two aspect completely.
Summary of the invention
The object of the present invention is to provide bile acid chelating agent or/and the application of vitamin D in preparation control non-alcohol fatty liver medicine.Vitamin D is by suppressing inflammatory reaction, suppressing lipid synthesis, and regulates enterohepatic circulation of bile acid, thereby reached, improves liver function, reduces liver fat and gathers, and reduces inflammation and strengthens the effect of liver regeneration.Bile acid chelating agent equally also can play adjusting enterohepatic circulation of bile acid, and then suppresses the effect that fatty liver occurs.Meanwhile, the two drug combination also has good synergism.
For achieving the above object, concrete technical scheme of the present invention is as follows:
Bile acid chelating agent is or/and vitamin D is prevented and treated the application in non-alcohol fatty liver medicine in preparation, and described vitamin D comprises the form of multivitamin D, as vitamin D2 (vitamin D
2), vitamin D3 (vitamin D
3), and there is bioactive vitamin D3 and derivant thereof.
Described have bioactive vitamin D3 and derivant is: calcitriol (calcitriol, 1,25 (OH)
2d3), other can activate the various derivative compounds of vitamin D receptor (VDR, vitamin D receptor), as 1 α-cacidol, calcifediol calcifediol, calcipotriol calcipotriol etc.
The instructions of taking of described calcitriol is: micro-gram/times of 0.25-2.5, and every day 1-2 time, oral; Or described calcitriol carries out intravenous injection by the following method: 0.005-0.5 microgram/kg body weight, every 1-3 time/week.
Described bile acid chelating agent comprises various forms of polyamine cation exchange resiies, is selected from cholestyramine or colestipol.
Described cholestyramine is for oral or take at table before the meal simultaneously, and 4-8 gram/times, every day 1-3 time, takes after mixing it with water, and every day, maximal dose was 24 grams.
Described colestipol is for oral before the meal, 2-8 gram/times, and every day 1-3 time, oral, every day, maximal dose was 30 grams.
Described bile acid chelating agent or vitamin D also can with fat-soluble A drug combination.Or, the medicine of described bile acid chelating agent or vitamin D and other antimetabolic syndromes, for example, the drug combinations such as metformin metformin, Statins statins, the special class fibrates of shellfish, nicotinic acid nicotinic acid, glitazone medicine.
Bile acid chelating agent of the present invention or/and the application of vitamin D in preparation control non-alcohol fatty liver medicine based on following result of study: (1) vitamin D deficiency not only can promote lipid synthesis, and can be used as " second strike " and promote inflammatory reaction etc. to cause non-alcohol fatty liver (NAFLD) excessive to non-alcoholic stellato-hepatitis (NASH).The present invention finds that vitamin D deficiency can start an inflammation of the liver, and fatty liver occurs; (2) the present invention finds that giving heavy dose of calcitriol can stop fatty liver to change fat hepatitis (NASH) into; (3) the present invention finds that enterohepatic circulation of bile acid is impaired and forms relevantly as liver and the minimizing of gall bladder bile acid content etc. and non-alcoholic stellato-hepatitis, and under prompting normal physiological state, in hepatocyte, bile acid can suppress lipid synthesis; (3) enterohepatic circulation of bile acid is impaired declines relevant with the heavy absorption and transport body of ileal bile acid ASBT expression; (4), during non-alcoholic stellato-hepatitis, ileum FGF15/19-liver SHP approach is abnormal; (5) thus vitamin D and cholestyramine can regulate enterohepatic circulation of bile acid to improve fatty liver; (6) prophylactic use vitamin D can effectively alleviate the fatty liver of high fat diet induction, expresses by SHP approach inhibition lipid synthesis relevant with promotion ileum FGF15/19; (7) bile acid chelating agent can be by promoting that FGF15/19 expresses to regulate liver lipid synthesis.
The outstanding technique effect of the present invention is:
1, bile acid chelating agent of the present invention or/and vitamin D in the application of preparation control non-alcohol fatty liver medicine, by the combination with intestinal bile acid, thereby reduced the absorption of lipid in fatty emulsifying and diet and in the deposition of liver, thereby in Pathophysiology level, thereby can improve liver function by regulating enterohepatic circulation of bile acid, reduce liver fat and gather, reduce inflammation and strengthen liver regeneration.
2, bile acid chelating agent of the present invention or/and vitamin D in the application of preparation control non-alcohol fatty liver medicine, after being combined with intestinal bile acid, liver bile acid biosynthesis increases, thereby activates liver Nei Fani ester X receptor (FXR) and then suppress endogenous fatty acid synthetic.That is, not only can reduce lipid emulsification and reduce lipid absorption, can also stimulate hepatic bile acid generation and then suppress lipid synthetic.Simultaneously, activated vitamin D or derivatives thereof also has the effect that regulates enterohepatic circulation of bile acid, vitamin D can heavily absorb by promoting intestinal bile acid absorption transporter ASBT to express increase bile acid intestinal, and then it is synthetic to suppress endogenous fatty acid, thereby alleviate non-alcohol fatty liver (inflammation).
Obviously, according to foregoing of the present invention, according to the ordinary skill of this area and customary means, not departing under the above-mentioned basic fundamental thought of the present invention prerequisite, can also make modification, replacement or the change of other various ways.
The specific embodiment of form, is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following examples, all technological means realizing based on foregoing of the present invention all belong to scope of the present invention.
Accompanying drawing explanation
Fig. 1 is the route map that vitamin D prevention non-alcoholic stellato-hepatitis suppresses lipid synthesis approach.
Fig. 2 is the route map of vitamin D to the mechanisms of therapeutic action of the fatty liver having formed.
Fig. 3 is that bile acid chelating agent regulates enterohepatic circulation of bile acid, affects the route map of lipid synthesis approach.
Fig. 4 A-C is that vitamin D deficiency promotes that fatty liver makes progress to non-alcoholic stellato-hepatitis, comparison diagram (A. HE and oil red O stain that after vitamin D, fatty liver improves; B. hepatic tissue content of triglyceride; C. weight of mice trendgram).
Fig. 5 A-B is that vitamin D deficiency inflammatory reaction strengthens, and suppresses comparison diagram (A. liver TNF and the IL-6 mrna expression situation of inflammatory reaction after vitamin D; B. pathology NAS scoring).
Fig. 6 A-C is that vitamin D deficiency and vitamin D express on liver and gall bladder bile acid content impact (A), ileum ASBT the comparison diagram that impact (B), hepatic CYP7A1 and CYP27A1 express (C) impact.
Fig. 7 A-B is that vitamin D deficiency and vitamin D are expressed the comparison diagram of impact (A), fatty acid oxidation impact (B) on liver SREBP-1C and FAS.
Fig. 8 A-C is that vitamin D of normal physiological state hemostasis is expressed the comparison diagram of impact on ileum FGF15/19, liver SHP, SREBP-1C and FAS.
Fig. 9 A-C is that vitamin D of normal physiological state hemostasis is expressed the comparison diagram of (B), liver F XR expression (C) impact on liver and gall bladder bile acid content (A), ileum ASBT, RXR.
Figure 10 A-C be cholestyramine on the fatty liver pathology of high fat diet induction change impact (A), to liver tg content influence (B), comparison diagram to weight of mice tendency influence (C).
Figure 11 A-D is that cholestyramine expresses on mechanism (A), liver and the gall bladder bile acid content (B) of lipid synthesis impact, ileum ASBT, FGF15 the comparison diagram that (C), hepatic CYP7A1 and SHP express (D) impact.
The specific embodiment
The application of vitamin D in preparation control non-alcohol fatty liver medicine
Vitamin D is selected calcitriol (Calcitriol), oral, micro-gram/times of 0.25-2.5, every day 1-2 time, the 2-24 month course for the treatment of.Or replace with vitamin D3, every day, 500-20000 IU, oral, 2-10 month.Effect can be passed judgment on according to following detection index and coherence check result.As detect index and comprise blood test biochemical indicator, glutamate pyruvate transaminase (AST), glutamic oxaloacetic transaminase, GOT (AST), total bilirubin, T-CHOL, triglyceride, high density lipoprotein, uric acid, blood glucose etc.Liver imaging is learned inspection and is comprised B ultrasonic, CT and MRI etc.The level of blood vitamin D (is generally 25-OH VD
3) also can be used as one of judging quota of effect.
The application of bile acid chelating agent in preparation control non-alcohol fatty liver medicine
Bile acid chelating agent is colestipol, and colestipol is for oral before the meal, 2-8 gram/times, and every day 1-3 time, every day, maximal dose was 30 grams, the 2-24 month course for the treatment of.Effect is determined by the assessment to fatty liver.
The application of bile acid chelating agent in preparation control non-alcohol fatty liver medicine
Bile acid chelating agent is cholestyramine, and cholestyramine is for oral or take at table before the meal simultaneously, and 4-8 gram/times, every day 1-3 time, takes after mixing it with water, and every day, maximal dose was 24 grams.The 2-24 month course for the treatment of.
embodiment 4
The application of bile acid chelating agent associating vitamin D in preparation control non-alcohol fatty liver medicine
Bile acid chelating agent is cholestyramine, and cholestyramine is for oral or take at table before the meal simultaneously, and 4-8 gram/times, every day 1-3 time, takes after mixing it with water, and every day, maximal dose was 24 grams; Vitamin D is oral in 2-4 hour after the meal, and 0.25 micro-gram/times, every day 1-2 time.The 2-24 month course for the treatment of.
The application of bile acid chelating agent associating vitamin D in preparation control non-alcohol fatty liver medicine
Bile acid chelating agent is colestipol, and colestipol is for oral before the meal, 2-8 gram/times, and every day 1-3 time, oral, every day, maximal dose was 30 grams; Vitamin D is oral in 2-4 hour after the meal, and 0.25 micro-gram/times, every day 1-2 time.The 2-24 month course for the treatment of.
The application of bile acid chelating agent in preparation control non-alcohol fatty liver medicine
Bile acid chelating agent is cholestyramine, and with fat-soluble A drug combination, oral dose when described fat-soluble A and bile acid chelating agent drug combination is: 3000IU.The 2-24 month course for the treatment of.
experimental example 1
vitamin D deficiency promotes the generation of fat hepatitis (NASH), and calcitriol suppresses the formation of fatty liver
1.1 laboratory animal
Babl/C mice is used in the experiment of SPF level, male, body weight 20-25g.Under room temperature (approximately 23 ℃), give laboratory animal ad lib and drinking-water, except VDD+HFD and VDD+HFD+D3 group mice has (referring to laboratory animal divides into groups and experimental design) special light as requested, all the other all mices are accepted the illumination of nature day and night change.
1.2 Models of Fatty Livers build
Give Babl/C mice high fat content (fat accounts for total calorie card 60%) forage feed 8 weeks, freely intake.
1.3 impacts of checking vitamin D on fatty liver
On above-mentioned model basis, according to DIFFERENT FEED and feeding patterns, be divided into following 5 groups (every group of n=8): 1. Normal group (control): give the normal fat content of well-balanced vitamin D (17%) forage feed 8 weeks, normal day and night change illumination; 2. common high fat diet group, model control group (High fat diet, HFD): give the high fat of well-balanced vitamin D (60%) forage feed 8 weeks, normal day and night change illumination; 3. common high fat diet+ 1,25 (OH)
2d3 injection group (HFD+D3): give the high fat of well-balanced vitamin D (60%) forage feed 8 weeks, normal day and night change illumination, starts to give 1,25 (OH) on the 3rd week
2d3 0.5 μ g/100g, intramuscular injection, twice to the 8th week weekly; 4. vitamin D deficiency high fat diet group (VDD+HFD): give the high fat of vitamin D deficiency (60%) forage feed 8 weeks, mouse cage covers ventilative lucifuge carton and carries out lucifuge processing; 5. vitamin D deficiency high fat diet+ 1,25 (OH)
2d3 injection group (VDD+HFD+D3): give the high fat of vitamin D deficiency (60%) forage feed 8 weeks, mouse cage covers ventilative lucifuge carton and carries out lucifuge processing, starts to give 1,25 (OH) on the 3rd week
2d3 0.5 μ g/100g, intramuscular injection, twice to the 8th week weekly.
1.4 experimental specimens are collected
Experiment mice is fed 8 weeks by above-mentioned condition, records weekly the growing states such as mice food-intake and body weight, hair color for twice, and HFD+D3 group and VDD+HFD+D3 group mice are injected for the last time D3 and put to death for 48 hours.Putting to death and within first 3 days, adjusting the feed cycle is feed in 12 hours between daytime, and fasting at 12 hours nights, freely drinks water.Put to death fasting in first 12 hours.
4% chloral hydrate intraperitoneal injection of anesthesia, anaesthetizes successfully rear fixedly mice, cuts off stomach wall, exposes abdominal cavity and liver.Postcava is got blood.Liver perfusion: folder closes postcava, cuts off portal vein, cuts off diaphram, exposes heart, right ventricle inserting needle, and 10ml normal saline pours into liver and is canescence.Take off complete liver, weigh.The 90-110mg hepatic tissue of accurately weighing extracts the acid of liver gallbladder; Careful separation is also taken off gallbladder and is detected cholic acid in gallbladder; The 30-50mg that accurately weighs extracts liver tg; Leave and take part liver (about 0.5*1cm) 4% formaldehyde and fixedly carry out pathologic finding; Leave and take part liver organization in OCT embedding; All the other livers are cut into about 100mg fritter and put to cryopreservation tube.Leave and take terminal ileum 5cm, remove surface fat, after flushing enteric cavity, put to cryopreservation tube.The liver organization of OCT embedding, fritter hepatic tissue and terminal ileum are organized and all after taking-up, are put immediately to 1-2 minute in liquid nitrogen, in afterwards-80 ℃ of refrigerators, preserve, and carry out respectively frozen section, mRNA or protein extraction.
1.5 test item
Pathology H & E and oil red O stain, hepatic tissue triglyceride levels, record body weight growth pattern etc. and understand the impact of vitamin D on fatty liver.And detect bile acid biosynthesis related gene CYP7A1, teleblem sodium dependency bile acid transport body (apical sodium dependent bile acid transporter, ASBT), farnesol X receptor (farnesoid X receptor, FXR), small difference dimer companion (small heterodimer partner, SHP), the mrna expression such as FGF15, liver and gall bladder bile sour water are flat, lipid metabolism relevant enzyme is as fatty acid synthetase (fatty acid synthase, FAS), hard ester acyl coenzyme A desaturase-1(stearoyl-CoA desaturase, SCD-1), peroxisome proliferator activated receptor-α (peroxisome proliferator activated-receptor-α, PPAR-α), carnitine transferring enzyme 1 α (carnitine palmitoyl transferase-1 α, CPT-1 α) and inflammatory factor tumor necrosis factor α (tumor necrosis factor-α, TNF-α) and interleukin-6 (interleukin-6, IL-6) mechanism that the detection such as mrna expression affects fatty liver to vitamin D is inquired into.
1.6 result
1.6.1 pathological examination shows, High-fat diet 8 weeks, and a large amount of fat of the visible hepatocyte of pathological staining becomes, and has necrosis and the change of balloon sample in cell infiltration, lobule, proves that non-alcoholic fatty liver disease forms (as shown in Figure 4 A).The further weight fat of high fat diet of vitamin D deficiency becomes and inflammatory reaction, there is early stage non-alcoholic stellato-hepatitis (non-alcoholic steatohepatitis, NASH) performance (as shown in Figure 4 A), gives the supplementary rear mouse liver steatosis of vitamin D and obviously alleviates (as shown in Figure 4 A).
1.6.2 NAS appraisal result (seeing Fig. 5 B), H & E coloration result draws through pathological evaluation analysis: control group mouse liver NAS scoring 0 minute; HFD group mice NAS scoring average mark divides 3.20 minutes (3.2 ± 0.32), according to diagnostic criteria, between NASH and NAFL; VDD+HFD group mice NAS scoring average mark approximately 5 minutes (5.00 ± 0.33) reaches NASH standard; HFD+D3 group mice NAS scoring average mark approximately 1.4 minutes (1.44 ± 0.32); VDD+HFD+D3 group mice NAS scoring average mark approximately 2 minutes (2.00 ± 0.33).
1.6.3 hepatic tissue triglyceride testing result (seeing Fig. 4 B): in 8 weeks hepatic tissues of liver High-fat diet, triglyceride gathers, the more common high fat diet group of vitamin D deficiency high fat diet group further increases, the rear triglyceride of vitamin D 3 gathers and alleviates, thereby has stoped the accumulation of triglyceride in liver.
1.6.4 different vitamin D levels are fed 8 weeks weight of mice curve display (seeing Fig. 4 C): weight of mice speed VDD+HFD group and HFD group are greater than control group mice; VDD+HFD group is greater than HFD group mice; HFD+D3 group increasess slowly compared with HFD group; VDD+HFD+D3 group increasess slowly compared with VDD+HFD group.Show that vitamin D deficiency can put on weight, and do not increase the absorption of calorie, and give calcitriol, suppressed the body weight that high fat diet brings and increase.
1.6.5 the result that affects that vitamin D is expressed inflammatory factor shows (seeing Fig. 5 A): under identical fat intake condition, during vitamin D deficiency, inflammatory factor TNF-α mrna expression further increases; Under High-fat diet, vitamin D 3 can suppress the expression of inflammatory factor TNF-α.The expression of IL-6mRNA and TNF-α have identical trend.
1.6.6 vitamin D shows (Fig. 6) to the result that affects of enterohepatic circulation of bile acid:
1), in identical fat intake situation, vitamin D deficiency mouse liver bile acid reduces.The vitamin D 3 liver Determination of Bile Acids (seeing Fig. 6 A) that can raise; In identical fat intake situation, the acid of vitamin D deficiency mice gall bladder bile reduces; The vitamin D 3 gall bladder bile acid content (seeing Fig. 6 A) that can raise.
2) terminal ileum ASBT expression (seeing Fig. 6 B): after high fat diet forms non-alcoholic fatty liver disease for 8 weeks, ileum ASBT expresses rising, and intestinal heavily absorbs bile acid to be increased.Vitamin D deficiency can suppress the expression of ileum ASBT, reduces intestinal bile acid absorption.Vitamin D 3 can promote ileum ASBT to express, and promotes bile acid absorption.
3) different vitamin D and fat content are fed and within 8 weeks, are respectively organized mice CYP7A1 and CYP27A1 expression (seeing Fig. 6 C): high fat diet forms after non-alcoholic fatty liver disease for 8 weeks, and liver bile acid biosynthesis is suppressed compared with control group mice.Vitamin D deficiency can promote the expression of hepatic CYP7A1, thereby raises the synthetic of bile acid.Vitamin D 3 can suppress CYP7A1 and express.Liver CYP27A1 expression: after high fat diet forms non-alcoholic fatty liver disease for 8 weeks, the bypass of liver bile acid biosynthesis activates.Vitamin D deficiency has no significant effect the expression of liver CYP27A1.Vitamin D 3 can suppress CYP27A1 and express.
1.6.7 vitamin D shows (Fig. 7) to the result that affects of lipid metabolism related gene: the impact of lipid synthesis gene (seeing Fig. 7 A), and SREBP-1C and FAS express and increase at High-fat diet for 8 weeks; During vitamin D deficiency, express further and increase; Vitamin D 3 can suppress its expression.Fatty acid oxidation related gene expression situation (seeing Fig. 7 B), CPT-1 α and PPAR-α result show: during vitamin D deficiency, fatty acid oxidation weakens; Vitamin D 3 can raise fatty acid oxidation, strengthens oxidative cleavage of fatty acids.
experimental example 2
Vitamin D (calcitriol) suppresses the synthesis system of liver fat acid
2.1 laboratory animals: with 1.1
2.2 experimental animal models: for the impact of research vitamin D on mice bile acid biosynthesis under normal physiological status, Babl/C mice is divided into Normal group (control, n=6) and 1,25 (OH) at random
2d3 injection group (D3, n=6).Two groups all give the normal fat diet of well-balanced vitamin D, and fasting is D3 mouse peritoneal injection 1,25 (OH) 2D3 1 μ g/100g body weight after 10 hours, and the dosage normal saline such as control group mice injection, put to death after 8 hours.
2.3 animals are processed and specimen collection: with 1.4
2.4 test items: carry out the mrna expressions such as CYP7A1, ASBT, FXR, SHP, FGF15 and liver and gall bladder bile acid horizontal detection.
2.5 result
2.5.1 after normal mouse injection vitamin D3, lipid metabolism related gene expression result shows (seeing Fig. 8 A-C): vitamin D3 injection group mouse intestinal FGF15 mrna expression obviously raises, liver SHP gene expression raises, and liver SREBP-1C and FAS express and decline.
2.5.2 Determination of Bile Acids result shows (seeing Fig. 9 A-C): liver Determination of Bile Acids declines, and gallbladder cholic acid content raises; Intestinal FXR and ASBT express and decline.Liver F XR up-regulated.
As can be seen here, normal mouse gives calcitriol in fasting after 10 hours, and after 8 hours, in liver, bile acid reserves decline, and bile acid in gallbladder obviously rises.ASBT in small intestinal, bile acid transport body and FXR, Farnesoid X receptor, is all downward trend, and in liver, FXR is the trend of rising.Therefore, the increase of liver sausage circulation will be conducive to the inhibition synthetic to liver fatty acid.
experimental example 3
For example, by polycaprolactam polyamine cation exchange resin (cholestyramine), stop the generation of fatty liver
3.1 laboratory animals: with 1.1
3.2 experimental animal models: be the further effect of checking bile acid in pathogenesis of fatty liver process, we have set up cholestyramine partly to test: model control group (High fat diet, HFD): processing method is the same; Common high fat diet+cholestyramine group (HFD+Cholestyramine): give to add after 3g cholestyramine mixes and feed mice 8 weeks in the normal high fat diet of every 100g, normal day and night change illumination.Every group of N=8.
3.3 animals are processed and specimen collection: with 1.4
3.4 detect index: pathology detect, detect blood fat, biochemistry, and hepatic tissue pathology, hepatic tissue content of triglyceride, hepatic tissue cholic acid content, gallbladder cholic acid content, endogenous fatty acid synthetase are expressed, CYP7A1 expresses and inflammatory factor expression.
3.5 result
3.5.1 histopathology shows (seeing Figure 10 A): the H & E accidental fat of visible high fat diet+cholestyramine group mouse liver cell that dyes becomes, be less than 33%, rare cell infiltration and lobule necrosis region, having no balloon sample becomes, take a turn for the better with the more fatty apparition of high fat diet group, almost approach Normal group.Oil red O stain also visible high fat diet+cholestyramine group fat drips compared with the obviously minimizing of HFD group, almost approaches normal.Pathological examination shows that cholestyramine has obvious inhibitory action to the non-alcoholic fatty liver disease of high fat diet induction.
3.5.2 hepatic tissue triglyceride result shows (seeing Figure 10 B): high fat diet+cholestyramine group obviously reduces compared with high fat diet group hepatic tissue triglyceride, approaches normal.Result is consistent with pathological examination, and proving again cholestyramine can suppress gathering of triglyceride in liver in High-fat diet process, alleviates fatty liver.
3.5.3 body weight gain trend result shows (seeing Figure 10 C): high fat diet+cholestyramine group slows down compared with high fat diet group body weight gain, even lower than normal control mice.
3.5.4 cholestyramine (bile acid chelating agent) is on the impact of 8 weeks mice bile acid biosynthesis of high fat diet (being shown in Figure 11 A): bile acid chelating agent on the one hand by and intestinal bile acid limit the absorption of triglyceride, on the other hand by suppressing the expression of intestinal FGF15, liver SHP is declined, cause liver Cyp7A1 to rise, bile acid biosynthesis increases, and the latter can suppress the synthetic of fatty acid.Moreover bile acid chelating agent rises the expression of ASBT in enterocyte, promotes the heavily absorption of bile acid.Bile acid chelating agent fills bile acid in gallbladder and liver.As feedback, the SHP of reduction rises SRBEP-1c, and FAS expresses increase.But the effect of integrating is the formation that has suppressed fatty liver.Meanwhile, after cholestyramine long-term disposal, the acid of endogenous bile acid is synthetic to be increased, and its consequence can suppress synthetic (the seeing Figure 11 B) of fatty acid.Thereby the effect that is cholestyramine is to be combined with intestinal bile acid to get rid of the heavily absorption of external minimizing bile acid, and then reduces the absorption of lipid.Therefore, the negative feedback of liver endogenous bile acid biosynthesis strengthens.Experiment show this negative feedback effect, high fat diet+cholestyramine group and the comparison of high fat diet group: liver bile acid biosynthesis key enzyme CYP7A1mRNA expresses 15 times (the seeing Figure 11 D) that obviously raise; Every gram of hepatic tissue Determination of Bile Acids raises 3 times.
3.5.5 cholestyramine shows (seeing Figure 11 D) to High-fat diet 8 weeks mice endogenous fatty acids, the synthetic results that affect of triglyceride: high fat diet+cholestyramine and the comparison of high fat diet group, endogenous fatty acid synthetase (FAS) obviously raises 4.3 times, and in triglyceride building-up process, one of crucial regulatory factor SREBP-1C is synthetic also obviously raises.Liver SHP expresses reduction.
3.5.6 cholestyramine affects result demonstration (seeing Figure 11 C) to ileum FGF15/19 and ASBT: cholestyramine can obviously reduce the FGF15 up-regulated of high fat diet induction.The ileum ASBT that simultaneously further raises high fat diet induction expresses, and promotes bile acid absorption.
As can be seen here, Balb/C mice (n=8) gives High-fat diet 8 weeks, the visible typical non-alcohol fatty liver performance of HE dyeing: periportal hepatic cell fattydegeneration and balloon sample become.In the high fat diet for the treatment of group mice, added cholestyramine (3% w/w), found that fatty apparition improvement almost all disappears.Oil red O stain has shown after High-fat diet in hepatocyte essence that a large amount of red fat drips dyeing equally, and after cholestyramine treatment, fat drips obvious minimizing.Equally, cholestyramine can reduce the reserves of liver tg, and reduces the body weight increase that high fat diet brings.
experimental example 4
Vitamin D prevention non-alcoholic stellato-hepatitis suppresses lipid synthesis approach
As shown in Figure 1, vitamin D, by promoting intestinal FGF15/19 to express, to liver, regulates fat anabolism through blood circulation.Vitamin D is by inducing intestinal to express FGF15/19, and the latter is combined with surface of hepatocytes receptor FGFR4, and induction SHP expresses, thereby suppresses SREBP1c, and synthesizes key gene as the expression of FAS and SCD-1 etc. with fatty acid.The FGF15/19 of vitamin D induction also can increase the expression of liver PPAR-alpha and CPT-1alpha, promotes fatty acid at mitochondrial oxidative metabolism, promotes energy expenditure, to reduce the savings of triglyceride in liver.Vitamin D can also induce the bile acid transport body surface of small intestine cells to reach, and promotes bile acid in the heavily absorption of intestinal.At liver, bile acid activates FXR induction SHP and expresses, and the latter and then inhibition CYP7A1 and lipid generate gene expression.
experimental example 5
The mechanisms of therapeutic action of vitamin D to the fatty liver having formed
As shown in Figure 2, vitamin D regulates to reduce by Promote immunity the chronic inflammatory disease that high fat diet causes.Vitamin D also can suppress SREBP-1c, thereby suppresses the synthetic of fatty acid.In the non-alcohol fatty liver of high fat diet induction, give the expression that vitamin D can promote intestinal bile acid transport body ASBT, promote bile acid in the heavily absorption of intestinal.Heavily absorb and increase the liver bile acid causing and reduce and can suppress lipid and generate related gene as the expression of FAS and SCD-1.On the other hand, vitamin D can be induced peroxisome proliferator-activated receptor alpha (PPAR-α), and PPAR-α can promote carnitine transferring enzyme (CTP-1) to express, and promotes fatty acid at mitochondrial oxidative metabolism.
experimental example 6
Bile acid chelating agent regulates enterohepatic circulation of bile acid, affects lipid synthesis approach
As shown in Figure 3, first, application bile acid chelating agent can reduce the emulsification of bile acid to lipid material, has reduced the absorption of triglyceride and the deposition of liver.The second, the temporary transient consumption of bile acid that bile acid chelating agent causes can promote the expression of liver bile acid biosynthesis key enzyme CYP7A1, increases the synthetic of liver bile acid.In hepatocyte, bile acid raises and can induce FXR to express and then induction small difference dimer SHP expression, and SHP can suppress the expression of CYP7A1 and some lipid synthesis related genes.Therefore, bile acid chelating agent can play simultaneously and reduce lipid absorption and deposition, suppresses endogenous fatty acid and the synthetic effect of triglyceride.
Claims (10)
1. bile acid chelating agent is or/and the application of vitamin D in preparation control non-alcohol fatty liver medicine.
2. bile acid chelating agent as claimed in claim 1, or/and vitamin D is prevented and treated the application in non-alcohol fatty liver medicine in preparation, is characterized in that: described vitamin D is selected from vitamin D2, vitamin D3 and has bioactive vitamin D3 and derivant thereof.
3. bile acid chelating agent as claimed in claim 2 is or/and the application of vitamin D in preparation control non-alcohol fatty liver medicine, it is characterized in that: described have bioactive vitamin D3 and derivant is: calcitriol, 1 α-cacidol, calcifediol or calcipotriol.
4. bile acid chelating agent as claimed in claim 3, or/and vitamin D is prevented and treated the application in non-alcohol fatty liver medicine in preparation, is characterized in that: the instructions of taking of described calcitriol is: micro-gram/times of 0.25-2.5, and every day 1-2 time, oral.
5. bile acid chelating agent as claimed in claim 3 is or/and the application of vitamin D in preparation control non-alcohol fatty liver medicine, it is characterized in that: the intravenous methods of described calcitriol is: 0.005-0.5 microgram/kg body weight, every 1-3 time/week.
6. bile acid chelating agent as claimed in claim 1, or/and vitamin D is prevented and treated the application in non-alcohol fatty liver medicine in preparation, is characterized in that: described bile acid chelating agent is cholestyramine or colestipol.
7. bile acid chelating agent as claimed in claim 6 is or/and the application of vitamin D in preparation control non-alcohol fatty liver medicine, it is characterized in that: described cholestyramine is for oral or take at table before the meal simultaneously, 4-8 gram/times, every day 1-3 time, take after mixing it with water, every day, maximal dose was 24 grams.
8. bile acid chelating agent as claimed in claim 6 is or/and the application of vitamin D in preparation control non-alcohol fatty liver medicine, it is characterized in that: described colestipol is for oral before the meal 2-8 gram/times, every day 1-3 time, oral, every day, maximal dose was 30 grams.
9. bile acid chelating agent as claimed in claim 1, or/and vitamin D is prevented and treated the application in non-alcohol fatty liver medicine in preparation, is characterized in that: described bile acid chelating agent or vitamin D, and with fat-soluble A drug combination.
10. bile acid chelating agent as claimed in claim 1 is or/and the application of vitamin D in preparation control non-alcohol fatty liver medicine, it is characterized in that: described bile acid chelating agent or vitamin D, with metformin, Statins, the special class of shellfish, nicotinic acid or the medication combined medication of glitazone.
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| US20180265463A1 (en) * | 2014-12-24 | 2018-09-20 | Kyoto University | Vitamin D3 Derivatives and Pharmaceutical Use Thereof |
| JP2021006577A (en) * | 2014-12-24 | 2021-01-21 | 国立大学法人京都大学 | Vitamin d3 derivative and pharmaceutical use thereof |
| JP7108356B2 (en) | 2014-12-24 | 2022-07-29 | 国立大学法人京都大学 | Vitamin D3 derivative and pharmaceutical use thereof |
| CN107613997A (en) * | 2015-01-18 | 2018-01-19 | 加维什-加利里生物应用有限公司 | The extract rich in vitamin D and its composition of edible fungus and their applications in the immune related disorder for the treatment of |
| CN106176800A (en) * | 2016-07-11 | 2016-12-07 | 韩源平 | The pharmacy application of polycation resin |
| CN106176800B (en) * | 2016-07-11 | 2019-12-06 | 韩源平 | Pharmaceutical application of polycation resin |
| CN114099540A (en) * | 2021-09-16 | 2022-03-01 | 成都施桂行医药科技有限责任公司 | Application of cationic polymer in preparation of medicine for removing intestinal microbial toxins and treating tumors |
| CN114099540B (en) * | 2021-09-16 | 2023-09-08 | 成都施桂行医药科技有限责任公司 | Application of cationic polymer in preparation of medicines for eliminating intestinal microbial toxins and treating tumors |
| CN114146184A (en) * | 2021-12-03 | 2022-03-08 | 成都施桂行医药科技有限责任公司 | Use of cationic polymers for the preparation of medicaments |
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