Emerging role of obeticholic acid in the management of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) is the commonest chronic liver disease and its prevalence is increasing driven by the pandemic of obesity and type 2 diabetes mellitus. NAFLD can progress to cirrhosis and is associated with increased risk for cardiovascular disease and hepatocellular cancer. Diet and exercise are limited by suboptimal long-term adherence in patients with NAFLD. On the other hand, current pharmacological treatment of NAFLD has limited efficacy and unfavorable safety profile. In this context, obeticholic acid(OCA), a selective agonist of the farnesoid X receptors, might represent a useful option in these patients. Preclinical studies suggest that OCA improves hepatic steatosis, inflammation and fibrosis. A proof-of-concept study and the randomized, placebo-controlled Farnesoid X Receptor Ligand Obeticholic Acid in non-alcoholic steatohepatitis Treatment(FLINT) trial also showed improvements in liver histology in patients with NAFLD who received OCA. Weight loss and reduction in blood pressure were also observed. However, the effects of OCA on insulin resistance are conflicting and the lipid profile is adversely affected by this agent. In addition, pruritus is frequently observed during treatment with OCA and might lead to treatment discontinuation. However, given the limitations of existing treatments for NAFLD, OCA might represent a useful therapeutic option in selected patients with NAFLD.

Obeticholic acid attenuates human immunodeficiency virus/alcohol metabolism-induced pro-fibrotic activation in liver cells

BACKGROUND The morbidity and mortality of human immunodeficiency virus(HIV)-infection is often associated with liver disease,which progresses slowly into severe liver dysfunction.There are multiple insults which exacerbate HIV-related liver injury,including HIV-associated dysregulation of lipid metabolism and fat turnover,coinfections with hepatotropic viruses and alcohol abuse.As we reported before,exposure of hepatocytes to HIV and alcohol metabolites causes high oxidative stress,impairs proteasomal and lysosomal functions leading to accumulation of HIV in these cells,which end-ups with apoptotic cell death and finally promotes development of liver fibrosis.AIM To study whether obeticholic acid(OCA)prevents HIV/ethanol metabolisminduced hepatotoxicity and subsequent activation of hepatic stellate cells(HSC)by HIV+apoptotic hepatocyte engulfment.METHODS Huh7.5-CYP(RLW)cells were exposed to HIV and acetaldehyde-generating system(AGS)in the presence or absence of OCA.In the cells,we measured the expression of HIV-related markers:HIVgagRNA-by real-time polymerase chain reaction(PCR),p24-by western blot,HIV DNA-by semi-nested PCR,integrated HIV DNA-by ddPCR.Lysosomal and proteasomal activities were measured using fluorometrically-labeled substrates.For hepatocyte apoptosis,cleaved caspase 3 and cleaved PARP were visualized by western blot and cytokeratin 18-by M30 ELISA-in supernatants.Apoptotic bodies were generated from untreated and HIV-treated RLW cells exposed to UV light.Pro-fibrotic activation of HSC was characterized by Col1A1 and transforming growth factor-βmRNAs,while inflammasome activation-by NLRP3,caspase 1,interleukin(IL)-6,IL-1βmRNA levels.RESULTS In RLW cells,OCA treatment attenuated HIV-AGS-induced accumulation of HIVgagRNA,HIV DNA and p24.OCA suppressed reactive oxygen species production and restored chymotrypsin-like proteasome activity as well as cathepsin B lysosome activity.OCA also decreased HIV-AGS-triggered apoptosis in RLW cells.Exposure of HIV-containing apoptotic hepatocytes to HSC prevented activation of inflammasome and induced pro-fibrotic activation in these cells.CONCLUSION We conclude that by suppressing oxidative stress and restoring proteasomal and lysosomal functions impaired by HIV and ethanol metabolism,OCA decreases accumulation of HIV in hepatocytes,leading to down-regulation of apoptosis in these cells.In addition,OCA reverses pro-fibrotic and inflammasome-related activation of HSC triggered by engulfment of HIV-containing apoptotic hepatocytes,potentially contributing to suppression of liver fibrosis development.

Precise delivery of obeticholic acid via nanoapproach for triggering natural killer T cell-mediated liver cancer immunotherapy

Primary bile acids were reported to augment secretion of chemokine(C-X-C motif)ligand16(CXCL16)from liver sinusoidal endothelial cells(LSECs)and trigger natural killer T(NKT)cellbased immunotherapy for liver cancer.However,abundant expression of receptors for primary bile acids across the gastrointestinal tract overwhelms the possibility of using agonists against these receptors for liver cancer control.Taking advantage of the intrinsic property of LSECs in capturing circulating nanoparticles in the circulation,we proposed a strategy using nanoemulsion-loaded obeticholic acid(OCA),a clinically approved selective farnesoid X receptor(FXR)agonist,for precisely manipulating LSECs for triggering NKT cell-mediated liver cancer immunotherapy.The OCA-nanoemulsion(OCA-NE)was prepared via ultrasonic emulsification method,with a diameter of 184 nm and good stability.In vivo biodistribution studies confirmed that the injected OCA-NE mainly accumulated in the liver and especially in LSECs and Kupffer cells.As a result,OCA-NE treatment significantly suppressed hepatic tumor growth in a murine orthotopic H22 tumor model,which performed much better than oral medication of free OCA.Immunologic analysis revealed that the OCA-NE resulted in augmented secretion of CXCL16 and IFN-g,as well as increased NKT cell populations inside the tumor.Overall,our research provides a new evidence for the antitumor effect of receptors for primary bile acids,and should inspire using nanotechnology for precisely manipulating LSECs for liver cancer therapy.

Current and emerging pharmacological therapy for nonalcoholic fatty liver disease

The main treatment of patients with non-alcoholic fatty liver disease(NAFLD) is life style modification including weight reduction and dietary regimen.Majority of patients are safely treated with this management and pharmacologic interventions are not recommended. However, a subgroup of NAFLD patients with non-alcoholic steatohepatitis(NASH) who cannot achieve goals of life style modification may need pharmacological therapy. One major obstacle is measurement of histological outcome by liver biopsy which is an invasive method and is not recommended routinely in these patients. Several medications, mainly targeting baseline mechanism of NAFLD, have been investigated in clinical trials for treatment of NASH with promising results. At present, only pioglitazone acting as insulin sensitizing agent and vitamin E as an antioxidant have been recommended for treatment of NASH by international guidelines. Lipid lowering agents including statins and fibrates, pentoxifylline, angiotensin receptor blockers, ursodeoxycholic acid, probiotics and synbiotics are current agents with beneficial effects for treatment of NASH but have not been approved yet. Several emerging medications are in development for treatment of NASH. Obeticholic acid, liraglutide, elafibranor, cenicriviroc and aramchol have been tested in clinical trials or are completing trials. Here in, current and upcoming medications with promising results in clinical trial for treatment of NAFLD were reviewed.

A combined nanotherapeutic approach targeting farnesoid X receptor,ferroptosis,and fibrosis for nonalcoholic steatohepatitis treatment

Obeticholic acid(OCA),a farnesoid X receptor(FXR)agonist with favorable effects on fatty and glucose metabolism,has been considered the leading candidate drug for nonalcoholic steatohepatitis(NASH)treatment.However,its limited effectiveness in resolving liver fibrosis and lipotoxicity-induced cell death remains a major drawback.Ferroptosis,a newly recognized form of cell death characterized by uncontrolled lipid peroxidation,is involved in the progression of NASH.Nitric oxide(NO)is a versatile biological molecule that can degrade extracellular matrix.In this study,we developed a PEGylated thiolated hollow mesoporous silica nanoparticles(MSN)loaded with OCA,as well as a ferroptosis inhibitor liproxsatin-1 and a NO donor S-nitrosothiol(ONL@MSN).Biochemical analyses,histology,multiplexed flow cytometry,bulk-tissue RNA sequencing,and fecal 16S ribosomal RNA sequencing were utilized to evaluate the effects of the combined nanoparticle(ONL@MSN)in a mouse NASH model.Compared with the OCA-loaded nanoparticles(O@MSN),ONL@MSN not only protected against hepatic steatosis but also greatly ameliorated fibrosis and ferroptosis.ONL@MSN also displayed enhanced therapeutic actions on the maintenance of intrahepatic macrophages/monocytes homeostasis,inhibition of immune response/lipid peroxidation,and correction of microbiota dysbiosis.These findings present a promising synergistic nanotherapeutic strategy for the treatment of NASH by simultaneously targeting FXR,ferroptosis,and fibrosis.

Clinical Updates in Primary Biliary Cholangitis:Trends,Epidemiology, Diagnostics, and New Therapeutic Approaches

Primary biliary cholangitis,formerly known as primary biliary cirrhosis,is a chronic,autoimmune,and cholestatic disease ameliorating the biliary epithelial system causing fibrosis and end-stage liver disease,over time.Patients range from an asymptomatic phase early in the disease course,to symp-toms of decompensated cirrhosis later in its course.This review focuses on the current consensus on the epidemiology,diagnosis,and management of patients with primary biliary cholangitis.We also discuss established medical manage-ment as well as novel and investigational therapeutics in the pipeline for management of PBC.

Future Pharmacotherapy for Non-alcoholic Steatohepatitis (NASH): Review of Phase 2 and 3 Trials

Non-alcoholic steatohepatitis(NASH)results from inflammation and hepatocyte injury in the setting of hepatic steatosis.Non-alcoholic steatohepatitis increases the risk of progression to liver fibrosis and cirrhosis,and is the most rapidly growing etiology for liver failure and indication for liver transplantation in the USA.Weight loss and lifestyle modification remain the standard first-line treatment,as no USA Food and Drug Administration-approved pharmacotherapy currently exists.The past decade has seen an explosion of interest in drug development targeting pathologic pathways in non-alcoholic steatohepatitis,with numerous phase 2 and 3 trials currently in progress.Here,we concisely review the major targets and mechanisms of action by class,summarize results from com-pleted pivotal phase 2 studies,and provide a detailed outline of key active studies with trial data for drugs in development,including obeticholic acid,elafibranor,cenicriviroc and selonsertib.

Drugs for Non-alcoholic Steatohepatitis (NASH): Quest for the Holy Grail

Nonalcoholic fatty liver disease (NAFLD) is a global epidemic that is likely to become the most common cause of chronic liver disease in the next decade, worldwide. Though numerous drugs have been evaluated in clinical trials, most of them have returned inconclusive results and shown poorly-tolerated adverse effects. None of the drugs have been approved by the Food and Drug Administration for treating biopsy-proven non-alcoholic steatohepatitis (NASH). Vitamin E and pioglitazone have been extensively used in treatment of biopsy-proven nondiabetic NASH patients. Although some amelioration of inflammation has been seen, these drugs did not improve the fibrosis component of NASH. Therefore, dietary modification and weight reduction have remained the cornerstone of treatment of NASH;moreover, they have shown to improve histological activity as well as fibrosis. The search for an ideal drug or ‘Holy Grail’ within this landscape of possible agents continues, as weight reduction is achieved only in less than 10% of patients. In this current review, we summarize the drugs for NASH which are under investigation, and we provide a critical analysis of their up-to-date results and outcomes.

Therapies for non-alcoholic steatohepatitis

Current phase 3 trials for the treatment of non-alcoholic steatohepatitis(NASH)are discussed in this review.Modalities that are based on weight loss include therapeutic lifestyle changes,pharmacological weight loss drugs(e.g.,orlistat),and bariatric surgery.Traditionally,insulin resistance has been targeted using pioglitazone,but liraglutide and elafibranor are emerging as potential treatments.With regard to the farnesoid X receptor(FXR)pathway,obeticholic acid has been approved for primary biliary cholangitis and is being studied as a treatment for NASH.Antioxidants include vitamin E and statins.Medications that target fibrogenesis directly instead of NASH include selonsertib.

Progress in the Management of Patients with Cholestatic Liver Disease:Where Are We and Where Are We Going?

Cholestatic liver disease is a group of diseases in which bile acid accumulates in the liver for various reasons,resulting in abnormal liver biochemical indicators and histological damage.Cholestasis can be divided into intrahepatic cholestasis and extrahepatic cholestasis,which will contribute to liver damage and progress to liver fibrosis and cirrhosis.Primary biliary cholangitis(PBC)and primary sclerosing cholangitis are the two most typical cholestatic liver diseases.Ursodeoxycholic acid is currently the first-line treatment for PBC,while obeticholic acid,budesonide and fibrates have also shown good potential in the treatment of PBC.There are currently no official drugs approved to treat primary sclerosing cholangitis,and the use of ursodeoxycholic acid may have certain clinical benefits.At present,progress has been made in new treatment directions for cholestatic liver disease,including fibroblast growth factor 19,cholestyramine,S-adenosyl-L-methionine,steroid drugs,farnesoid X receptor agonists,and more.Considerable progress has been made in the management of cholestatic liver disease but there are still many opportunities and challenges.In this review,we summarized the recommended guidelines for the management of cholestatic disease and the progress of new drug research and development,in order to provide an important reference for the clinical practice of cholestatic liver disease.