Therapies For Nonalcoholic Steatohepatitis Research Articles

Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis

Enhanced de novo lipogenesis mediated by sterol regulatory element–binding proteins (SREBPs) is thought to be involved in nonalcoholic steatohepatitis (NASH) pathogenesis. In this study, we assessed the impact of SREBP inhibition on NASH and liver cancer development in murine models. Unexpectedly, SREBP inhibition via deletion of the SREBP cleavage–activating protein (SCAP) in the liver exacerbated liver injury, fibrosis, and carcinogenesis despite markedly reduced hepatic steatosis. These phenotypes were ameliorated by restoring SREBP function. Transcriptome and lipidome analyses revealed that SCAP/SREBP pathway inhibition altered the fatty acid (FA) composition of phosphatidylcholines due to both impaired FA synthesis and disorganized FA incorporation into phosphatidylcholine via lysophosphatidylcholine acyltransferase 3 (LPCAT3) downregulation, which led to endoplasmic reticulum (ER) stress and hepatocyte injury. Supplementation with phosphatidylcholines significantly improved liver injury and ER stress induced by SCAP deletion. The activity of the SCAP/SREBP/LPCAT3 axis was found to be inversely associated with liver fibrosis severity in human NASH. SREBP inhibition also cooperated with impaired autophagy to trigger liver injury. Thus, excessively strong and broad lipogenesis inhibition was counterproductive for NASH therapy; this will have important clinical implications in NASH treatment.

Non-alcoholic fatty liver disease and type 2 diabetes mellitus. II. Treatment

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease. Non-alcoholic steatohepatitis (NASH), the aggressive form of NAFLD can progress to cirrhosis, and is becoming the leading cause of end-stage liver disease. NAFLD and NASH are prevalent in obese individuals and frequently coexist with type 2 diabetes mellitus as well as cardiovascular and renal complications. There is no approved therapy for the treatment of NAFLD and NASH. Their current management focuses on controlling risk factors, and lifestyle modification, weight reduction, caloric restriction, diet and exercise, but these can be difficult to achieve and maintain. Thus, there is an urgent need for effective pharmacotherapy. This review summarizes pharmacological agents available to treat diabetes mellitus, the main risk factor of NAFLD, drugs that could potentially be useful also for the therapy of NASH. Furthermore, we describe novel therapies targeting different pathogenic pathways of NAFLD, several agents that are under development specifically for the treatment of NASH. These new classes of medications may target hepatic fat accumulation, de novo lipogenesis, farnesoid X receptor-bile acid axis, oxidative stress, inflammation, gut microbiome and fibrogenesis. Until now, the use of pioglitazone and vitamin E has only been recommended by guidelines for selected patient groups with biopsy-proven NASH. It is likely that in the future, the combination of different types of targeted pharmacotherapies will provide an effective treatment for NASH. Since NAFLD is a systemic metabolic disease, cooperation between diabetologists, nephrologists, cardiologists and hepatologists is also highly advised in the management of these patients.

Spermidine Ameliorates Nonalcoholic Steatohepatitis through Thyroid Hormone-Responsive Protein Signaling and the Gut Microbiota-Mediated Metabolism of Bile Acids

Spermidine, a natural polyamine and physiological autophagy inducer, is involved in various physiological processes. However, the impact and mechanism of spermidine on nonalcoholic steatohepatitis (NASH) remains unclarified. We found that daily spermidine intake was significantly lower in volunteers with liver dysfunction than the healthy controls, and the serum and fecal spermidine levels were negatively correlated with the NASH phenotypes. Spermidine supplementation significantly attenuated hepatic lipid accumulation, insulin resistance, hepatic inflammation, and fibrosis in NASH mice induced by a western diet. The ameliorating effect of spermidine on lipid accumulation might be partly regulated by thyroid hormone-responsive protein (THRSP) signaling and autophagy. Moreover, spermidine altered the profile of hepatic bile acids (BAs) and microbial composition and function. Furthermore, spermidine reversed the progression of hepatic steatosis, inflammation, and fibrosis in mice with preexisting NASH. Therefore, spermidine ameliorates NASH partly through the THRSP signaling and the gut microbiota-mediated metabolism of BAs, suggesting that spermidine might be a viable therapy for NASH.

Caffeine Ameliorates AKT-Driven Nonalcoholic Steatohepatitis by Suppressing De Novo Lipogenesis and MyD88 Palmitoylation.

Dysregulated hepatic lipogenesis represents a promising druggable target for treating nonalcoholic steatohepatitis (NASH). This work aims to evaluate the therapeutic efficacy of caffeine in a NASH mouse model displaying increased hepatic lipogenesis driven by constitutive hepatic overexpression of the active v-akt murine thymoma viral oncogene homolog (AKT). Caffeine was administered in the AKT mice to study the efficacy in vivo. AKT-transfected and insulin-stimulated human hepatoma cells were used for in vitro experiments. The results demonstrated that caffeine ameliorated hepatic steatosis and inflammatory injury in vivo. Mechanistically, caffeine repressed the AKT/mTORC1 and SREBP-1/ACC/FASN signaling in mice and in vitro. Furthermore, caffeine impaired NF-κB activation by stabilizing IκBα, resulting in a reduction of proinflammatory mediators interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α). Notably, caffeine abolished mTORC1/FASN-dependent MyD88 palmitoylation, which could be essential for its anti-inflammatory potential. Collectively, these results suggest that caffeine consumption could be advantageous in the prevention and therapy of NASH, especially in the subset accompanied by increased de novo lipogenesis.

Abstract 145: Glycine Metabolism Links Atherosclerosis And NASH: Studies In Humans, Nonhuman Primates And Mice

A major cause of death in patients with nonalcoholic steatohepatitis (NASH) is cardiovascular disease driven by accelerated atherosclerosis. The mechanisms linking NASH and atherosclerosis remain unclear and there is an urgent need to identify new pathways as targets for NASH without increasing, and preferably while decreasing, atherosclerosis. Lower circulating glycine is emerging as a common feature in both atherosclerosis and NASH, but the mechanisms behind reduced glycine, its potential as a causative factor and a therapeutic target are unclear. Applying unbiased transcriptomics and metabolomics, we uncovered impaired glycine biosynthesis in humans and mice with atherosclerosis and NASH. Hepatic glycine biosynthetic genes were downregulated with a most significant suppression of alanine-glyoxylate aminotransferase ( AGXT ). Functional deficiencies of AGXT lead to oxalate accumulation and we found decreased glycine/oxalate ratio in both NASH and atherosclerosis. In mice, dietary and genetic ( Agxt –/– and Agxt -/- / Apoe -/- ) approaches to limit glycine availability exacerbated NASH and atherosclerosis with suppressed hepatic fatty acid β-oxidation (FAO) and enhanced inflammation as the underlying pathways. These effects were reversed by glycine supplementation and AAV8-mediated AGXT overexpression. We explored glycine-based compounds as potential therapies for atherosclerosis and NASH and identified a tripeptide (Gly-Gly-L-Leu, DT-109) that protected mice from NASH and atherosclerosis by modulating FAO, glutathione synthesis and the gut microbiome. We further developed a dietary model in cynomolgus monkeys that closely mimics human NASH. DT-109 ameliorated NASH and showed anti-atherogenic properties in monkeys by modulating similar pathways observed in the mice. Altogether, impaired glycine metabolism links atherosclerosis and NASH and can be targeted for the simultaneous treatment of these diseases.

Rifaximin Ameliorates Non-alcoholic Steatohepatitis in Mice Through Regulating gut Microbiome-Related Bile Acids.

Non-alcoholic steatohepatitis (NASH) is the progressive stage of non-alcoholic fatty liver disease (NAFLD). The non-absorbable antibiotic rifaximin has been used for treatment of irritable bowel syndrome, traveling diarrhea, and hepatic encephalopathy, but the efficacy of rifaximin in NASH patients remains controversial. This study investigated the effects and underlying mechanisms of rifaximin treatment in mice with methionine and choline deficient (MCD) diet-induced NASH. We found that rifaximin greatly ameliorated hepatic steatosis, lobular inflammation, and fibrogenesis in MCD-fed mice. Bacterial 16S rRNA sequencing revealed that the gut microbiome was significantly altered in MCD-fed mice. Rifaximin treatment enriched 13 amplicon sequence variants (ASVs) belonging to the groups Muribaculaceae, Parabacteroides, Coriobacteriaceae_UCG-002, uncultured Oscillospiraceae, Dubosiella, Rikenellaceae_RC9_gut_group, Mucispirillum, and uncultured Desulfovibrionaceae. However, rifaximin treatment also reduced seven ASVs in the groups Aerococcus, Oscillospiraceae, uncultured Ruminococcaceae, Bilophila, Muribaculaceae, Helicobacter, and Alistipes in MCD-fed mice. Bile acid-targeted metabolomic analysis indicated that the MCD diet resulted in accumulation of primary bile acids and deoxycholic acid (DCA) in the ileum. Rifaximin delivery reduced DCA levels in MCD-fed mice. Correlation analysis further showed that DCA levels were associated with differentially abundant ASVs modulated by rifaximin. In conclusion, rifaximin may ameliorate NASH by decreasing ileal DCA through alteration of the gut microbiome in MCD-fed mice. Rifaximin treatment may therefore be a promising approach for NASH therapy in humans.

Non-Alcoholic Steatohepatitis (NASH): An Update

Non-alcoholic Steatohepatitis (NASH) is a globally rising, multifactorial disease which may be a result of obesity, diabetes (type-2), hypercholesteremia and gut dysbiosis. NASH is characterized by inflammation and fibrosis of liver tissues which further leads to hepatocellular carcinoma or liver failure. Patients with non-alcoholic fatty liver disease (NAFLD) show symptoms of NASH in which the fat accumulation in the liver exceeds 5-10%. Accumulation of this fat in the form of triglyceride in the hepatocytes is the key factor for the development of NASH. This may be caused due to increase in the flow of fatty acid and de novo lipogenesis. This abnormal retention of fat leads to lipotoxicity, which can cause apoptosis, necrosis, inflammation and an increase in oxidative stress. Since the pathological factors associated with NASH are unclear, the treatment to control the progression and management of the disease is cumbersome. Progress is being made in order to understand the cellular and molecular mechanisms associated with the pathogenesis of this condition. With studies reporting that NASH is the most common liver disease after hepatitis C, there is an increase in the demands for medical therapy and diagnosis of NASH. However, no treatment has been proven to be effective for long-term use. Gut dysbiosis, major pathways involved in NASH progression, experimental animal models and the current therapeutic strategies for NASH is discussed in the present review.

Dihydroartemisinin alleviates steatosis and inflammation in nonalcoholic steatohepatitis by decreasing endoplasmic reticulum stress and oxidative stress

Nonalcoholic steatohepatitis (NASH) is a severely inflammatory subtype of nonalcoholic fatty liver. Endoplasmic reticulum stress (ERS) and oxidative stress (OS) cause metabolic abnormalities, promote liver steatosis and inflammation, and are central to the development of NASH. Dihydroartemisinin (DHA) is a compound extracted from Artemisia annua that is often used in the treatment of malaria. Recent studies have shown that DHA also has a wide range of pharmacological effects, acting on various organs throughout the body to exert anti-inflammatory, antioxidant, and anti-fibrotic effects. In this study, we demonstrated in vitro that the anti-inflammatory effect of DHA is effective against NASH and reduces liver steatosis. DHA treatment decreased the synthesis of lipids, such as cholesterol and free fatty acids, and the expression of nuclear factor kappa-B. This is accomplished by inhibiting the unfolded protein response and reducing the production of reactive oxygen species, thereby inhibiting OS and ERS. This study reveals DHA’s therapeutic effect and potential mechanism in NASH, implying that DHA could be a new and promising candidate for NASH therapy.

Transcriptomics Reveals Discordant Lipid Metabolism Effects between In Vitro Models Exposed to Elafibranor and Liver Samples of NAFLD Patients after Bariatric Surgery.

Background and aims: Non-alcoholic steatohepatitis (NASH) is a life-threatening stage of non-alcoholic fatty liver disease (NAFLD) for which no drugs have been approved. We have previously shown that human-derived hepatic in vitro models can be used to mimic key cellular mechanisms involved in the progression of NASH. In the present study, we first characterize the transcriptome of multiple in vitro NASH models. Subsequently, we investigate how elafibranor, which is a peroxisome proliferator-activated receptor (PPAR)-α/δ agonist that has recently failed a phase 3 clinical trial as a potential anti-NASH compound, modulates the transcriptome of these models. Finally, we compare the elafibranor-induced gene expression modulation to transcriptome data of patients with improved/resolved NAFLD/NASH upon bariatric surgery, which is the only proven clinical NASH therapy. Methods: Human whole genome microarrays were used for the transcriptomics evaluation of hepatic in vitro models. Comparison to publicly available clinical datasets was conducted using multiple bioinformatic application tools. Results: Primary human hepatocytes (PHH), HepaRG, and human skin stem cell-derived hepatic progenitors (hSKP-HPC) exposed to NASH-inducing triggers exhibit up to 35% overlap with datasets of liver samples from NASH patients. Exposure of the in vitro NASH models to elafibranor partially reversed the transcriptional modulations, predicting an inhibition of toll-like receptor (TLR)-2/4/9-mediated inflammatory responses, NFκB-signaling, hepatic fibrosis, and leukocyte migration. These transcriptomic changes were also observed in the datasets of liver samples of patients with resolved NASH. Peroxisome Proliferator Activated Receptor Alpha (PPARA), PPARG Coactivator 1 Alpha (PPARGC1A), and Sirtuin 1 (SIRT1) were identified as the major common upstream regulators upon exposure to elafibranor. Analysis of the downstream mechanistic networks further revealed that angiopoietin Like 4 (ANGPTL4), pyruvate dehydrogenase kinase 4 (PDK4), and perilipin 2 (PLIN2), which are involved in the promotion of hepatic lipid accumulation, were also commonly upregulated by elafibranor in all in vitro NASH models. Contrarily, these genes were not upregulated in liver samples of patients with resolved NASH. Conclusion: Transcriptomics comparison between in vitro NASH models exposed to elafibranor and clinical datasets of NAFLD patients after bariatric surgery reveals commonly modulated anti-inflammatory responses, but discordant modulations of key factors in lipid metabolism. This discordant adverse effect of elafibranor deserves further investigation when assessing PPAR-α/δ agonism as a potential anti-NASH therapy.

New avenues for NASH therapy by targeting ACC

Acetyl-CoA carboxylase (ACC) is one of the more promising therapeutic targets for non-alcoholic steatohepatitis (NASH), but current ACC inhibitors already tested in clinical trials also exert the unwanted adverse side effect of hypertriglyceridemia. In two recent studies by Calle etal. in Nature Medicine and Zhang etal. in Science Translational Medicine, new strategies for ACC targeting were explored for NASH therapy that successfully resolved the adverse effect of hyperlipidemia while maintaining potent anti-NASH efficacy. These findings bring encouraging new momentum to the clinical application of ACC inhibition for NASH therapy.

Evaluation of the Mechanism of Modified Lingguizhugan Decoction in the Treatment of Nonalcoholic Fatty Liver Disease.

Nonalcoholic steatohepatitis (NASH) may develop into cirrhosis and liver cancer, which imposes a great burden to individuals and society. Lingguizhugan decoction is a commonly used dampness dispelling medication in traditional Chinese medicine and is often used to treat those with phlegm and retained fluid from various causes and pathogeneses. The objective of this study was to explore the effect and mechanism of modified Lingguizhugan decoction (MLGZG) on lipid metabolism and the inflammatory response to identify a theoretical basis to promote its clinical application in NASH therapy. After treatment with MLGZG for 8 weeks, the weight of high-fat-diet (HFD)-fed NASH rats was significantly higher than that of rats in the normal group, and the weights in each dose group were significantly lower than those in the model group. The treatment groups (low, medium, and high doses) had different degrees of improvement in the changes in hepatocyte tissue structure, steatosis, and inflammatory infiltration. Compared with that in the normal group, the expression of TNF receptor-associated factor-3 (TRAF-3) and nuclear factor κB (NFκB) in the model group significantly increased to varying degrees. Compared with the NASH group, the treatment groups (low, middle, and high doses) showed modified lipid metabolism gene expression and decreased inflammatory factor expression levels. Modified Lingguizhugan decoction can improve the general condition of rats with nonalcoholic fatty liver disease by reducing the expression levels of TRAF3, NF-κB, the Toll-like receptor 4 (TLR-4) pathway, and related proteins, as well as the expression levels of lipid metabolism genes and cytokines.

Сравнительное исследование эффективности препарата Прогепар у пациентов с неалкогольным стеатогепатитом

Неалкогольная жировая болезнь печени (НАЖБП) является одним из самых распространенных заболеваний печени в развитых странах. В среднем ее частота достигает 20 %. У части пациентов ­НАЖБП протекает с наличием воспаления, вакуолизации гепатоцитов и последующим развитием фиброза и цирроза. Такой вариант течения НАЖБП называют неалкогольным стеатогепатитом (НАСГ). Пациенты с НАСГ подвержены более высокому риску развития осложнений, например возникновению гепатоцеллюлярной карциномы или варикозного расширения вен пищевода. Специфическая терапия НАСГ на сегодняшний день еще не разработана. Основные рекомендации для пациентов заключаются в изменении стиля жизни, что имеет определенную эффективность в снижении уровня стеатоза и активности воспаления. Однако быстро прогрессирующее течение НАСГ не всегда возможно контролировать одним только снижением калорийности диеты и увеличением уровня физической активности. Для лечения пациентов с НАСГ также используется неспецифическая терапия, которая способна замедлять прогрессирование заболевания и снижать уровень воспаления. Так как основным механизмом патогенеза НАСГ является оксидативный стресс, исследователи активно изучают действие различных антиоксидантов и их комбинаций. На сегодняшний день представлено большое количество результатов исследований подобных препаратов. Существенным ограничением большой части данных исследований является отсутствие тщательного мониторинга комплайенса и длительности выполнения пациентами рекомендаций по изменению образа жизни. Ведь в данной ситуации особый интерес должны представлять именно те пациенты, у которых высокая степень активности НАСГ сохраняется, несмотря на строгую приверженность к рекомендациям по изменению стиля жизни. В связи с этим требуется проведение дополнительных исследований по оценке эффективности фармакологической терапии у пациентов с НАСГ на фоне длительного изменения образа жизни. В этой статье мы приведем описание и результаты одноцентрового контролируемого исследования по оценке эффективности препарата Прогепар у пациентов с НАСГ с персистенцией активности воспалительного процесса на фоне модификации образа жизни.

Drug Therapy for Non-Alcoholic Steatohepatitis-Induced Liver Fibrosis

Aim. An overview of current pharmacotherapy for non-alcoholic steatohepatitis (NASH)-associated liver fibrosis.Key points. In current clinical recommendations, therapeutic measures in non-alcoholic fatty liver disease should include lifestyle change, body weight normalisation, NASH-associated liver fibrosis-specific drug therapy and treatment for metabolic syndrome-related diseases. Given a lack of approved antifibrotic therapies in NASH, several drugs have nevertheless demonstrated an adequate efficacy and safety in phase 3 clinical trials, also in compensated cirrhosis, which allows their practical validation in phase 4.Conclusion. The understanding of liver fibrosis as an adverse natural consequence of non-alcoholic fatty liver disease clearly attests for an early introduction and wide use of antifibrotic therapy to improve NASH outcomes and avoid associated complications.

A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques.

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease and has become a leading indication for liver transplantation in the United States. The development of effective therapies for NASH is a major unmet need. Here, we identified a small molecule, IMA-1, that can treat NASH by interrupting the arachidonate 12-lipoxygenase (ALOX12)–acetyl-CoA carboxylase 1 (ACC1) interaction. IMA-1 markedly blocked diet-induced NASH progression in both male mice and Cynomolgus macaque therapeutic models. The anti-NASH efficacy of IMA-1 was comparable to ACC inhibitor in both species. Protein docking simulations and following functional experiments suggested that the anti-NASH effects of IMA-1 were largely dependent on its direct binding to a pocket in ALOX12 proximal to its ACC1-interacting surface instead of inhibiting ALOX12 lipoxygenase activity. IMA-1 treatment did not elicit hyperlipidemia, a known side effect of direct inhibition of ACC enzymatic activity, in both mice and macaques. These findings provide proof of concept across multiple species for the use of small molecule–based therapies for NASH.

TAZ-induced Cybb contributes to liver tumor formation in non-alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is a leading cause of hepatocellular carcinoma (HCC), but mechanisms linking NASH to eventual tumor formation remain poorly understood. Herein, we investigate the role of TAZ/WWTR1, which is induced in hepatocytes in NASH, in the progression of NASH to HCC. The roles of hepatocyte TAZ and its downstream targets were investigated in diet-induced and genetic models of NASH-HCC using gene-targeting, adeno-associated virus 8 (AAV8)-H1-mediated gene silencing, or AAV8-TBG-mediated gene expression. The biochemical signature of the newly elucidated pathway was probed in liver specimens from humans with NASH-HCC. When hepatocyte-TAZ was silenced in mice with pre-tumor NASH using AAV8-H1-shTaz (short-hairpin Taz), subsequent HCC tumor development was suppressed. In this setting, the tumor-suppressing effect of shTaz was not dependent of TAZ silencing in the tumors themselves and could be dissociated from the NASH-suppressing effects of shTaz. The mechanism linking pre-tumor hepatocyte-TAZ to eventual tumor formation involved TAZ-mediated induction of the NOX2-encoding gene Cybb, which led to NADPH-mediated oxidative DNA damage. As evidence, DNA damage and tumor formation could be suppressed by treatment of pre-tumor NASH mice with AAV8-H1-shCybb; AAV8-TBG-OGG1, encoding the oxidative DNA-repair enzyme 8-oxoguanine glycosylase; or AAV8-TBG-NHEJ1, encoding the dsDNA repair enzyme non-homologous end-joining factor 1. In surrounding non-tumor tissue from human NASH-HCC livers, there were strong correlations between TAZ, NOX2, and oxidative DNA damage. TAZ in pre-tumor NASH-hepatocytes, via induction of Cybb and NOX2-mediated DNA damage, contributes to subsequent HCC tumor development. These findings illustrate how NASH provides a unique window into the early molecular events that can lead to tumor formation and suggest that NASH therapies targeting TAZ might also prevent NASH-HCC. Non-alcoholic steatohepatitis (NASH) is emerging as the leading cause of a type of liver cancer called hepatocellular carcinoma (HCC), but molecular events in pre-tumor NASH hepatocytes leading to HCC remain largely unknown. Our study shows that a protein called TAZ in pre-tumor NASH-hepatocytes promotes damage to the DNA of hepatocytes and thereby contributes to eventual HCC. This study reveals a very early event in HCC that is induced in pre-tumor NASH, and the findings suggest that NASH therapies targeting TAZ might also prevent NASH-HCC.

Abstract 10784: Circulating Obesity Associated Pro-Fibrotic Protein Promotes Fibrosis in Liver and Heart

Introduction: Non-alcoholic steatohepatitis (NASH), driven by the obesity epidemic, has become the most common form of liver disease. Obesity contributes inflamed visceral adipose tissue secretes pro-inflammatory adipokines that is causal for systemic metabolic disorders. Despite its importance, the mechanism of NASH in the presence of morbid obesity related adipokines from BAT remains unclear. Hypothesis: Various kinds of white adipokines are known in obesity. However, brown adipokines still remain to be explored. Methods: To identify the function of obesity associated pro-fibrotic protein (OAFP), we generated a murine obese NASH model by imposing a high fat diet in C57BL6/NCr mice, and murine systemic OAFP knockout (KO) model. We also conducted functional in vitro studies with differentiated brown adipocytes. Results: Analyzing two sets of DNA microarray data with bioinformatics, we identified a secreted form OAFP expressed in dysfunctional brown adipose tissue (BAT) in mice. Testing our biobank samples, we found this protein increased in plasma of NASH patients or aged individuals. We generated a murine obese NASH model by imposing a high fat diet in C57BL6/NCr mice, and found that OAFP is produced predominantly by BAT. In this model, we also found that OAFP increased in plasma. For this reason, we generated a murine systemic OAFP knockout (KO) model and found that liver fibrosis ameliorated in OAFP-KO model. In addition, vaccination therapy also inhibited liver fibrosis. In contrast, liver fibrosis augmented in OAFP gain of function (GOF) model, and these results suggested that OAFP has causal role for the progression of fibrotic response in liver. In the obese NASH model, we found that cardiac fibrosis also developed and this ameliorated in OAFP-KO model, indicating that OAFP may have pathological roles for heart failure with preserved ejection fraction (HFpEF) related with age-related disorders. In vitro studies with differentiated brown adipocytes showed that OAFP was upregulated through by PERK/JNK/c-fos/AP1 pathways. Conclusions: Our results suggest that OAFP contributes for the progression of fibrotic responses in obese or aged models. Inhibition of OAFP may become a therapy for NASH or HFpEF.

Repositioning of a novel GABA-B receptor agonist, AZD3355 (Lesogaberan), for the treatment of non-alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is a rising health challenge, with no approved drugs. We used a computational drug repositioning strategy to uncover a novel therapy for NASH, identifying a GABA-B receptor agonist, AZD3355 (Lesogaberan) previously evaluated as a therapy for esophageal reflux. AZD3355’s potential efficacy in NASH was tested in human stellate cells, human precision cut liver slices (hPCLS), and in vivo in a well-validated murine model of NASH. In human stellate cells AZD3355 significantly downregulated profibrotic gene and protein expression. Transcriptomic analysis of these responses identified key regulatory nodes impacted by AZD3355, including Myc, as well as MAP and ERK kinases. In PCLS, AZD3355 down-regulated collagen1α1, αSMA and TNF-α mRNAs as well as secreted collagen1α1. In vivo, the drug significantly improved histology, profibrogenic gene expression, and tumor development, which was comparable to activity of obeticholic acid in a robust mouse model of NASH, but awaits further testing to determine its relative efficacy in patients. These data identify a well-tolerated clinical stage asset as a novel candidate therapy for human NASH through its hepatoprotective, anti-inflammatory and antifibrotic mechanisms of action. The approach validates computational methods to identify novel therapies in NASH in uncovering new pathways of disease development that can be rapidly translated into clinical trials.

Narrative review of current and emerging pharmacological therapies for nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is the most common cause of chronic liver disease today, and it has now emerged as the leading etiology of end-stage liver disease requiring liver transplantation. It is a progressive form of non-alcoholic fatty liver disease which can not only progress to cirrhosis of liver and hepatocellular carcinoma (HCC), but is associated with increased cardiovascular risks too. Despite all the advances in the understanding of the risk factors and the pathogenetic pathways involved in the pathogenesis and progression of NASH, an effective therapy for NASH has not been developed yet. Although lifestyle modifications including dietary modifications and physical activity remain the mainstay of therapy, there is an unmet need to develop a drug or a combination of drugs which can not only reduce the fatty infiltration of the liver, but also arrest the development and progression of fibrosis and advancement to cirrhosis of liver and HCC. The pharmacologic therapies which are being developed target the various components believed to be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD)/NASH which includes insulin resistance, lipid metabolism oxidative stress, lipid peroxidation, inflammatory and cell death pathways, and fibrosis. In this review, we summarize the current state of knowledge on pharmacotherapy of NASH, and also highlight the recent developments in the field, for optimizing the management and treatment of NASH.

Therapeutic Potential of G Protein-Coupled Receptors Against Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH), the advanced stage of nonalcoholic fatty liver disease (NAFLD), affects approximately 6% of the population worldwide and is strongly associated with cardiometabolic disorders, placing subjects at a sharply increased risk of end-stage hepatic diseases and extrahepatic symptoms. Despite the importance of NASH, no NASH-specific drugs have been approved by the FDA. G protein-coupled receptors (GPCRs), which represent the largest group of druggable targets in the human genome, strongly regulate pathophysiological events. Recent structural and molecular studies have further expanded upon the classic pharmacological applications of GPCRs and enabled the use of emerging GPCR agonists or antagonists for the treatment of metabolic diseases. These advances have encouraged new insights regarding the development of GPCR-targeted NASH therapies. In this review, we analyze up-to-date reports of GPCRs in NASH and discuss trends in the use of GPCRs as targets for NASH treatment.

Non-Alcoholic Steatohepatitis (NASH) - A Review of a Crowded Clinical Landscape, Driven by a Complex Disease.

Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD), characterized by chronic inflammation and accumulation of fat in liver tissue. Affecting estimated 35 million people globally, NASH is the most common chronic liver condition in Western populations, and with patient numbers growing rapidly, the market for NASH therapy is projected to rise to $27.2 B in 2029. Despite this clinical need and attractive commercial opportunity, there are no Food and Drug Administration (FDA)-approved therapies specifically for this disease. Many have tried and unfortunately failed to find a drug, or drug combination, capable of unravelling the complexities of this metabolic condition. At the time of writing this review, only Zydus Cadila’s new drug application for Saroglitazar had been approved (2020) for NASH therapy in India. However, it is hoped that this dearth of therapy options will improve as several drug candidates progress through late-stage clinical development. Obeticholic acid (Intercept Pharmaceuticals), Cenicriviroc (Allergan), Aramchol (Galmed Pharmaceuticals), Resmetirom (Madrigal Pharmaceuticals), Dapagliflozin and Semaglutide (Novo Nordisk) are in advanced Phase 3 clinical trials, while Belapectin (Galectin Therapeutics), MSDC-0602K (Cirius Therapeutics), Lanifibranor (Inventiva), Efruxifermin (Akero) and Tesamorelin (Theratechnologies) are expected to start Phase 3 trials soon. Here, we have performed an exhaustive review of the current therapeutic landscape for this disease and compared, in some detail, the fortunes of different drug classes (biologics vs small molecules) and target molecules. Given the complex pathophysiology of NASH, the use of drug combination, different mechanisms of actions and the targeting of each stage of the disease will likely be required. Hence, the development of a single therapy for NASH seems challenging and unlikely, despite the plethora of later stage trials due to report. We therefore predict that clinical, patient and company interest in pipeline and next-generation therapies will remain high for some time to come.