Animal Models Of Liver Injury Research Articles

Liver and Metformin: Lessons of a fructose diet in mice

Studies show that the continuous consumption of fructose can lead to nonalcoholic fatty liver disease (NAFLD) and steatohepatitis. We aimed to investigate the role of Metformin in an animal model of liver injury caused by fructose intake, focusing on the molecular markers of lipogenesis, beta-oxidation, and antioxidant defenses. Male three months old C57BL/6 mice were divided into control group (C) and fructose group (F, 47% fructose), maintained for ten weeks. After, the groups received Metformin or vehicle for a further eight weeks: control (C), control + Metformin (CM), fructose (F), and fructose + Metformin (FM). Fructose resulted in hepatic steatosis, insulin resistance and lower insulin sensitivity in association with higher mRNA levels of proteins linked with de novo lipogenesis and increased lipid peroxidation. Fructose diminished mRNA expression of antioxidant enzymes, and of proteins responsible for mitochondrial biogenesis. Metformin reduced de novo lipogenesis and increased the expression of proteins related to mitochondrial biogenesis, thereby increasing beta-oxidation and decreasing lipid peroxidation. Also, Metformin upregulated the expression and activity of antioxidant enzymes, providing a defense against increased reactive oxygen species generation. Therefore, a significant reduction in triglyceride accumulation in the liver, steatosis and lipid peroxidation was observed in the FM group. In conclusion, fructose increases de novo lipogenesis, reduces the antioxidant defenses, and diminishes mitochondrial biogenesis. After an extended period of fructose intake, Metformin treatment, even in continuing the fructose intake, can reverse, at least partially, the liver injury and prevents NAFLD progression to more severe states.

Augmenter of liver regeneration protects against carbon tetrachloride-induced liver injury by promoting autophagy in mice.

BackgroundAugmenter of liver regeneration (ALR) exerts strong hepatoprotective properties in various animal models of liver injury, but its protective mechanisms have not yet been explored. Autophagy is a recently recognized rudimentary cellular response to inflammation and injury. The aim of this study was to test the hypothesis that ALR may protect against acute liver injury through the autophagic pathway.MethodsThe level and role of ALR in liver injury were studied in a mouse model of acute liver injury induced by carbon tetrachloride (CCl4). The effect of ALR on autophagy was analyzed in vitro and in vivo. After autophagy was inhibited by 3-methyladenine (3-MA), apoptosis and proliferation were detected in the mouse model with acute liver injury. The ALR and autophagic levels were measured in patients with liver cirrhosis (LC) and acute liver failure (ALF), respectively.ResultsDuring the progression of acute liver injury, the ALR levels increased slightly in early stage and significantly decreased in late stage in mice Treatment with an ALR plasmid via tail vein injection protected mice against acute liver injury. The protective effect of ALR relied on the induction of autophagy, which was supported by the following evidence: (1) ALR overexpression directly induced autophagy flux in vitro and in vivo; and (2) ALR treatment suppressed apoptosis and promoted proliferation in mice exposed to CCl4, but the inhibition of autophagy reversed these effects. More importantly, the ALR levels decreased in patients with LC and ALF compared with normal controls.ConclusionWe demonstrated that ALR ameliorated liver injury via an autophagic mechanism, which indicates a potential therapeutic application for liver injury.

Inducible Nitric Oxide Synthase Expression in Liver Injury: Liver Protective Effects on Primary Rat Hepatocytes.

Following injury to the liver, liver cells, including Kupffer cells and hepatocytes express inducible nitric oxide synthase (iNOS), followed by the production of excess levels of nitric oxide (NO). NO produced by iNOS has been found to contribute to liver injury. Treatment of primary cultures of rat hepatocytes with the proinflammatory cytokine interleukin (IL)-1β stimulated iNOS expression and NO production. Experiments with this in vitro hepatocyte model of liver injury and with in vivo animal models of liver injury have demonstrated that drugs showing a liver-protective effect in vivo also inhibited the induction of iNOS expression and NO production both in vivo and in vitro. Thus, in this in vitro hepatocyte model, the prevention of iNOS expression and NO production are considered indicators of liver protection. This review describes a simple in vitro liver injury model, consisting of IL-1β-stimulated cultured hepatocytes, and methods used to analyze the mechanisms of action of drugs that inhibit iNOS expression. This in vitro hepatocyte model may be used to assess the liver-protective effects of pharmaceutical agents, herbal medicines, and certain types of foods.

Hesperidin Alleviates Oxidative Stress and Upregulates the Multidrug Resistance Protein 2 in Isoniazid and Rifampicin-Induced Liver Injury in Rats.

ABSTRACTIsoniazid (INH) and rifampicin (RFP), two front‐line drugs used in tuberculosis therapy, may lead to seriously hepatotoxicity. The current study was carried out to investigate the hepatoprotective effects of hesperidin against INH‐ and RFP‐induced oxidative damage. The liver injury animal model of rats was induced by INH (75 mg/kg) and RFP (150 mg/kg) coadministration for 7 days, and hesperidin, at the dose of 50, 100, and 200 mg/kg, was orally administered to rats 2 h before INH and RFP administration. The biochemical and pathologic examinations were performed after rats were sacrificed. Moreover, the serum and liver glutathione (GSH), glutathione disulfide (GSSG), malondialdehyde (MDA), GSH peroxidase, and GSSG reductase were determined by test kits, and the expression of multidrug resistance proteins 2 (Mrp2) was determined by Western blotting and immunohistochemistry. The results showed that hesperidin significantly alleviated liver injury as indicated by the decreased levels of ALT, AST, bilirubin, total bile acid, and glutathione peroxidase and the increased levels of the GSH/GSSG ratio and the expression of Mrp2. Moreover, hesperidin could effectively reduce the pathological tissue damage. These results indicate that hesperidin can attenuate INH‐ and RFP‐induced oxidative damage, and the underlying mechanism may have correlation with its effect on the upregulation of Mrp2.

Th17 involvement in nonalcoholic fatty liver disease progression to non-alcoholic steatohepatitis.

The nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD encompasses a wide histological spectrum ranging from benign simple steatosis to non-alcoholic steatohepatitis (NASH). Sustained inflammation in the liver is critical in this process. Hepatic macrophages, including liver resident macropaghes (Kupffer cells), monocytes infiltrating the injured liver, as well as specific lymphocytes subsets play a pivotal role in the initiation and perpetuation of the inflammatory response, with a major deleterious impact on the progression of fatty liver to fibrosis. During the last years, Th17 cells have been involved in the development of inflammation not only in liver but also in other organs, such as adipose tissue or lung. Differentiation of a naïve T cell into a Th17 cell leads to pro-inflammatory cytokine and chemokine production with subsequent myeloid cell recruitment to the inflamed tissue. Th17 response can be mitigated by T regulatory cells that secrete anti-inflammatory cytokines. Both T cell subsets need TGF-β for their differentiation and a characteristic plasticity in their phenotype may render them new therapeutic targets. In this review, we discuss the role of the Th17 pathway in NAFLD progression to NASH and to liver fibrosis analyzing different animal models of liver injury and human studies.

Quantitative analysis of contrast-enhanced ultrasonography in acute radiation-induced liver injury: An animal model.

The aim of the present study was to examine and assess contrast-enhanced ultrasound in the early diagnosis of acute radiation-induced liver injury in a rat model. Sixty female rats were used, with 50 rats being utilized to produce an animal model of liver injury with a single dose of stereotactic X-ray irradiation of 20 Gy. Ten rats from the injury group and 2 rats from the control group were randomly selected on days 3, 7, 14, 21 and 28, and examined by contrast-enhanced ultrasound and histopathology of liver specimens. The rats were divided into four groups: the normal control group, mild, moderate, and severe radioactive liver injury groups based on the histopathological examination results. Hepatic artery arriving time (HAAT) and hepatic vein arriving time (HVAT) were recorded, and hepatic artery to vein transit time (HA-HVTT) was calculated. The time-intensity curve of liver parenchyma, the time to peak (TTP) and peak intensity (PI) were also obtained. Significant differences were observed between liver injury and control groups for PI and HA-HVTT (P<0.05). PI and HA-HVTT were shorter in the severe liver injury group compared to the mild and moderate liver injury groups (P<0.05). Compared to the control group, higher TTP was recorded in all the liver injury groups (P<0.05), and the highest TTP level was observed in the severe liver injury group compared to the mild or moderate group (P<0.05). However, no significant difference was observed between the mild and moderate groups for PI, HA-HVTT and TTP. In conclusion, the results showed that contrast-enhanced ultrasonography is useful for an earlier diagnosis in a rat model of acute radiation-induced liver injury.

AMPK dependent protective effects of metformin on tumor necrosis factor-induced apoptotic liver injury

Tumor necrosis factor α (TNF-α)-induced cellular apoptosis represents a common pathological mechanism underlying the progression of various liver disorders. Recently studies revealed that the anti-diabetic metformin provided protective benefits in several animal models of liver injury. In the present study, the potential modulatory effects of metformin on TNF-α-dependent apoptotic liver damage was investigated in mice with TNF-α/d-galactosamine (D-Gal)-induced liver injury. The results indicated that treatment with metformin significantly suppressed the elevation of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the activation of caspase cascade and the induction of cleaved caspase-3. Morphological analysis showed that metformin alleviated histopathological abnormalities and reduced TUNEL-positive apoptotic cells. Co-administration of the AMPK inhibitor compound C completely abolished the inhibitory effects of metformin on caspase cascade activation, significantly reversed the beneficial effects of metformin on histopathological abnormalities and hepatocytes apoptosis, and partially abolished the suppressive effects of metformin on plasma ALT elevation. These data indicated that metformin effectively alleviated TNF-α/D-Gal-induced apoptotic liver injury and these beneficial effects were at least partially mediated by AMPK.

Epigenetic Alterations of IL-6/STAT3 Signaling by Placental Stem Cells Promote Hepatic Regeneration in a Rat Model with CCl4-induced Liver Injury.

BackgroundHuman chorionic plate-derived mesenchymal stem cells (CP-MSCs) isolated from the placenta have been reported to demonstrate therapeutic effects in animal models of liver injury; however, the underlying epigenetic mechanism of this effect has not been elucidated. Thus, we investigated whether CP-MSCs influence epigenetic processes during regeneration of the injured liver.MethodsCP-MSCs were engrafted into a carbon tetrachloride (CCl4)-injured rat model through direct transplantation into the liver (DTX), intrasplenic transplantation (STX), and intravenous transplantation via the tail vein (TTX). Non-transplanted (NTX) rats were maintained as sham controls. Liver tissues were analyzed after transplantation using immunohistochemistry, western blot analysis, and quantitative methylation-specific polymerase chain reaction. Proliferation and human interleukin-6 (hIL-6) enzyme-linked immunosorbent assays were performed using CCl4-treated hepatic cells that were co-cultured with CP-MSCs.ResultsThe Ki67 labeling index, cell cyclins, albumin, IL-6, and gp130 levels were elevated in the CP-MSC transplantation groups. The concentration of hIL-6 in supernatants and the proliferation of CCl4-treated rat hepatic cells were enhanced by co-culturing with CP-MSCs (p<0.05), while the methylation of IL-6/IL-6R and STAT3 by CP-MSC transplantation decreased.ConclusionThese results suggest that administration of CP-MSCs promotes IL-6/STAT3 signaling by decreasing the methylation of the IL-6/SATA3 promoters and thus inducing the proliferation of hepatic cells in a CCl4-injured liver rat model. These data advance our understanding of the therapeutic mechanisms in injured livers, and can facilitate the development of cell-based therapies using placenta-derived stem cells.

Chinese herbal medicine modified Yu ping feng San Formula for treatment of Allergic Rhinitis in Children: a systematic review

Purpose: CGX is a modification of a traditional Korean herbal medicine, which is under clinical trial phase III for hepatofibrosis therapeutic effect. The objective is to present the status for CGX development regarding its clinical backgrounds, pharmacological studies in animal models, and current process of randomized clinical trial. Methods: CGX has been used for patients suffering various liver diseases, including chronic viral hepatitis and alcoholic liver disorders. The safety of CGX was evaluated in animalbased repeated toxicological studies using rats and beagle dogs. The pharmacological actions against hepatic fibrosis were evidenced in various chronic liver injury animal models using chemicals (CCl4, DMN, or TAA), chronic alcohol consumption, choline-deficient (MCD) diet, and bile duct ligation (BDL) respectively. It is now under a ramdomized controlled multicenter trial.phase III for hepatofibrosis. Results: The total number of participants is 174 in 2 Hospitals, who are suffering from chronic HBV, HCV or Alcoholic liver disease. The inclusion criteria is patientswith LSM5.5 kPa to 16kPa, aged between 18∼75 year. The exclusion criteria is the conditions of too severe status as follows; ascites, esophageal varix, TB > 3mg/dl, AST, ALT > ULN > 5 folds, INR > 2.0 or platelet 30. The drug treatment period is 6 months for 3 groups (placebo, 1gram or 2 gram of CGX daily). The primary measurement is the changed value of LSM (liver stiffness mesurement) during 6 months, and the secondary measurements are the changed value of hyaluronic acid (HA), serumTGF1, PDGF, AST to platelet ratio index (APRI) and QOL (SF-36) respectively. Conclusion: It is expected that multi-sites clinical trial evidences the fibro-therapeutic effects of CGX in patients with chronic viral or alcoholic liver diseases. Contact: Chang Gue Son, ckson@dju.ac.kr

Clinical Trial for Anti-hepatofibrotic Efeect of a Traditional Korean Formula (CGX) in Patients with Chronic Liver Disease

Purpose: CGX is a modification of a traditional Korean herbal medicine, which is under clinical trial phase III for hepatofibrosis therapeutic effect. The objective is to present the status for CGX development regarding its clinical backgrounds, pharmacological studies in animal models, and current process of randomized clinical trial. Methods: CGX has been used for patients suffering various liver diseases, including chronic viral hepatitis and alcoholic liver disorders. The safety of CGX was evaluated in animalbased repeated toxicological studies using rats and beagle dogs. The pharmacological actions against hepatic fibrosis were evidenced in various chronic liver injury animal models using chemicals (CCl4, DMN, or TAA), chronic alcohol consumption, choline-deficient (MCD) diet, and bile duct ligation (BDL) respectively. It is now under a ramdomized controlled multicenter trial.phase III for hepatofibrosis. Results: The total number of participants is 174 in 2 Hospitals, who are suffering from chronic HBV, HCV or Alcoholic liver disease. The inclusion criteria is patientswith LSM5.5 kPa to 16kPa, aged between 18∼75 year. The exclusion criteria is the conditions of too severe status as follows; ascites, esophageal varix, TB > 3mg/dl, AST, ALT > ULN > 5 folds, INR > 2.0 or platelet 30. The drug treatment period is 6 months for 3 groups (placebo, 1gram or 2 gram of CGX daily). The primary measurement is the changed value of LSM (liver stiffness mesurement) during 6 months, and the secondary measurements are the changed value of hyaluronic acid (HA), serumTGF1, PDGF, AST to platelet ratio index (APRI) and QOL (SF-36) respectively. Conclusion: It is expected that multi-sites clinical trial evidences the fibro-therapeutic effects of CGX in patients with chronic viral or alcoholic liver diseases. Contact: Chang Gue Son, ckson@dju.ac.kr

Recent advances in the development of farnesoid X receptor agonists.

Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing.

Alpha-lipoic acid exerts a liver-protective effect in acute liver injury rats

BackgroundRecent evidence indicates that alpha-lipoic acid (α-LA) has a variety of liver-protective effects through the suppression of inflammatory mediators including tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS). However, there are few reports that α-LA markedly enhanced the survival rate in animal models of liver injury with more than 90% death. The aim of this study was to investigate the beneficial effects of α-LA in a rat model of acute liver injury and to clarify the mechanisms of α-LA action. MethodsRats were treated with d-galactosamine and lipopolysaccharide (GalN and LPS) to induce acute liver injury. α-LA (100 mg/kg) was administered intraperitoneally 1 h before GalN and LPS injection. Inflammatory mediators including TNF-α and iNOS were analyzed. ResultsA single injection of α-LA improved the survival rate by more than 80%. α-LA prevented serum transaminase increases, histopathologic changes, and apoptosis in the liver. In the serum, α-LA decreased TNF-α production and increased interleukin (IL)-10 production. In the liver, α-LA reduced TNF-α and IL-6 messenger RNA (mRNA) but enhanced IL-10 mRNA. α-LA decreased the expression of iNOS mRNA and its antisense transcript, leading to the reduction of iNOS protein expression and resulting in the inhibition of nitric oxide production. An electrophoretic mobility shift assay revealed that α-LA reduced the activation of nuclear factor-kappa B induced by GalN and LPS. Conclusionsα-LA inhibited the induction of inflammatory mediators, such as TNF-α and iNOS, in part through the inhibition of nuclear factor-kappa B activation and enhanced the induction of IL-10. α-LA may have therapeutic potential for use in the prevention of acute liver injury.

CCL20 mediates lipopolysaccharide induced liver injury and is a potential driver of inflammation and fibrosis in alcoholic hepatitis

ObjectiveChemokines are known to play an important role in the pathophysiology of alcoholic hepatitis (AH), a form of acute-on-chronic liver injury frequently mediated by gut derived lipopolysaccharide (LPS). In our...

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The effect of ginsenosides on hepatogenic differentiation using placenta-derived stem cells as an in vitro screening system

Placenta-derived stem cells (PDSCs) isolated from human full-term placentas are able to grow through self-renewal and differentiate into multiple lineages. PDSCs have been reported to have a potential for hepatogenic differentiation and therapeutic effects in an animal model of liver injury. However, the frequency of the hepatogenic differentiation of PDSCs remains low. Saponins are a class of chemical compounds called glycosides and have various activities, including anti-inflammatory actions, anti-tumor effects, and anti-allergy and hepatoprotective activity. Because little is known about the effect of various ginsenosides on PDSC differentiation, we evaluated whether ginsenosides could induce the hepatogenic differentiation of PDSCs. PDSCs cultured under several different ginsenosides were induced to differentiate into hepatogenic lineages and were then analyzed. We found that the morphologies changed from a spindle shape to a characteristic polygonal hepatocyte-like morphology after hepatogenic differentiation induction. In addition, the differentiated cells expressed several hepatocyte-specific markers and increased their indocyanine green (ICG) uptake, although different efficacies for hepatogenic differentiation were observed according to the different ginsenoside conditions. Taken together, these data suggest that ginsenosides may contribute to enhanced hepatogenic differentiation of PDSCs and that PDSCs may be used as a source for in vitro drug screening.

Efficacy of chorionic plate-derived mesenchymal stem cells isolated from placenta in CCl4-injured rat liver depends on transplantation routes

The capability to engraft into degenerative environment or damaged tissues is considered crucial to maximize the therapeutic effect of stem cells in tissue regeneration. Human chorionic plate-derived mesenchymal stem cells (CP-MSCs) isolated from the placenta have been reported to have therapeutic effects in animal models of liver injury. However, the effect of transplantation route has not been evaluated. Thus, we investigated to identify optimal transplantation conditions of CP-MSCs for functional recovery of injured liver. PKH26 labeled CP-MSCs was engrafted into carbon tetrachloride (CCl4)-injured rat model through direct transplantation into the liver (DTP), intrasplenic transplantation (STP), and intravenous transplantation via the tail vein (TTP). Non transplanted (NTP) rats were maintained as sham controls. Serum and liver tissues were analyzed post 1-, 2-, 3-week after transplantation. The engraftment of cells was higher in DTP and STP group until 3-week post transplantation. In blood chemistry, the levels of glutamate-oxaloacetate transaminase (GOT/AST), glutamate-pyruvate transaminase (GPT/ALT) and total bilirubin (TBIL) in DTP and STP rats were significantly decreased compare to those of NTP rats (p < 0.01). In addition, the expression and deposition of type I collagen in DTP and STP rats was significantly reduced when they compared with NTP animals (p < 0.01). Therapeutic efficacy was better in DTP and STP rats than in TTP group. These results suggest that the administration of CP-MSCs via STP is an effective way for their therapeutic potential. These results provide useful guidelines for the application of basic transplantation technology to the cell therapy of liver disease using placenta-derived stem cells.

The best-laid plans

The best-laid plans

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We agree with Dr. Coombes and Dr. Syn that Hedgehog (Hh) signaling may be an important factor influencing liver regeneration, and in particular the development of the ductular reaction and progenitor cell expansion. We have not particularly assessed the Hh signaling in patients with alcoholic hepatitis. Studies have shown that hedgehog-responsive progenitor cells proliferate in liver injury and accumulate in humans with alcoholic liver disease correlating with disease severity.1, 2 This observation is particularly interesting because Hh signaling has been shown to participate in progenitor cell activation and proliferation in adults and to induce hepatoblast proliferation during embryogenesis, but has to be shut off to allow hepatoblast commitment and differentiation.3 These findings suggest that Hh signaling may be implicated in the accumulation of progenitor cells in the liver, promoting proliferation and preventing differentiation. Although inhibition of Hh signaling seems to reduce progenitor cell response and liver regeneration in animal models of liver injury, the role of these cells in liver regeneration is not yet completely understood, and the contribution of Hh-responsive progenitor cells to newly generated hepatocytes has not been elucidated. Further studies are warranted to elucidate this question. The association of inflammation with progenitor cell proliferation has been described but has never been investigated in alcoholic hepatitis. We agree that inflammation and progenitor cell proliferation are key events in alcoholic hepatitis, thus its relationship should be specifically investigated. In our study it was not possible to investigate the inflammatory cell populations infiltrating the damaged liver, but the overall quantification of inflammatory cells by standard histological methods did not show a positive correlation with progenitor cell expansion and mortality. The results of our study raise the question whether liver progenitor cell expansion is a marker of liver injury in acute-on-chronic conditions or the result of an inefficient liver regeneration attempt. The assessment of liver progenitor cell expansion and differentiation in human samples together with mechanistic studies in relevant animal models of liver injury will help in understanding the role of progenitor cells in liver regeneration and disease outcome and its contribution to liver repair. Pau Sancho-Bru M.D.*, José Altamirano M.D.*, Ramon Bataller M.D.*, * Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain.

Perspective: TGR5 (Gpbar-1) in liver physiology and disease

Bile acids are signaling molecules with diverse endocrine functions. Bile acid effects are mediated through the nuclear receptor farnesoid X receptor (FXR), the G-protein coupled receptor TGR5 (Gpbar-1) and various other bile acid sensing molecules. TGR5 is almost ubiquitously expressed and has been detected in different non-parenchymal cells of human and rodent liver. Here, TGR5 has anti-inflammatory, anti-apoptotic and choleretic functions. Mice with targeted deletion of TGR5 are protected from the development of cholesterol gallstones. Administration of specific TGR5 agonists lowers serum and liver triglyceride levels thereby reducing liver steatosis. Furthermore, activation of TGR5 promotes intestinal glucagon-like peptide-1 (GLP-1) release, thereby modulating glucose homeostasis and energy expenditure in brown adipose tissue and skeletal muscle. Additionally, TGR5 exerts anti-inflammatory actions resulting in decreased liver injury in animal models of sepsis. These beneficial effects make TGR5 an attractive therapeutic target for metabolic diseases, such as diabetes, obesity, atherosclerosis and steatohepatitis.

Potential drug mechanism(s) targeting the contractile status of hepatic stellate cells

Potential drug mechanism(s) targeting the contractile status of hepatic stellate cells