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

ABSTRACT: 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.

SUBMITTER: Sharma M

PROVIDER: S-EPMC7868704 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Sharma Mithun M Premkumar Madhumita M Kulkarni Anand V AV Kumar Pramod P Reddy D Nageshwar DN Rao Nagaraja Padaki NP

Journal of clinical and translational hepatology 20201209 1

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 extens ...[more]

PMID: 33604254

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Project description:The mechanisms underlying the progression of non-alcoholic steatohepatitis (NASH) are not completely elucidated. In this study we have integrated gene expression profiling of liver biopsies of NASH patients with translational studies in a mouse model of steatohepatitis and with pharmacological interventions in isolated hepatocytes to identify a novel mechanism implicated in the pathogenesis of NASH. By using high-density oligonucleotide microarray analysis we identified a significant enrichment of known genes involved in the multi-step catalysis of long chain polyunsaturated fatty acids, including delta-5 and 6 desaturases. A combined inhibitor of delta-5 and delta-6 desaturases significantly reduced intracellular lipid accumulation and inflammatory gene expression in isolated hepatocytes. Gas chromatography analysis revealed impaired delta-5 desaturase activity toward the omega-3 pathway in livers from mice with high-fat diet (HFD)-induced NASH. Consistently, restoration of omega-3 index in transgenic fat-1 mice expressing an omega-3 desaturase, which allows the endogenous conversion of omega-6 into omega-3 fatty acids, produced a significant reduction in hepatic insulin resistance, hepatic steatosis, macrophage infiltration and necroinflammatory liver injury, accompanied by attenuated expression of genes involved in inflammation, fatty acid uptake and lipogenesis. These results were comparable to those obtained in a group of mice receiving a HFD supplemented with EPA/DHA. Of interest, hepatocytes from fat-1 mice or supplemented with EPA exhibited synergistic anti-steatotic and anti-inflammatory actions with the delta-5/ delta-6 inhibitor. Conclusion: These findings indicate that both endogenous and exogenous restoration of the hepatic balance between omega-6 and omega-3 fatty acids and/or modulation of desaturase activities exert preventive actions in NASH. The complete database comprised the expression measurements of 18185 genes for liver sample groups: 8 non-alcoholic steatohepatitis (NASH ) and 7 control samples. This dataset is part of the TransQST collection.

Project description:BackgroundThe eggs of head lice are fixed to the hair of their hosts by means of a persistent glue-like fixative that is not chemically bound to the substrate. Eggshells stuck to hairs after successfully treating the infestation are a cosmetic issue and a source of misunderstanding about whether the infestation is eliminated. Hitherto, no effective treatment to loosen louse eggs and nits has been found.MethodsAn extensive screening of surface active compounds, oils, esters, and other cosmetic lubricants used a slip-peel device to measure the forces required to release the grip of the fixative. Promisingly effective compounds were formulated into suitable carriers for further testing. The most effective combination formulation was tested, as a commercial product (Hedrin Stubborn Egg Loosening Lotion), in a usage study of 15 children with nits, in which one half of the head was combed only on damp hair and the other half combed after a 10 min treatment using the product.ResultsLaboratory tests of the forces required to remove nits found that pelagonic acid derivatives, particularly isononyl isononanoate, in the presence of a polymeric gelling agent and water, were most effective to reduce the initial grip of the fixative as well as reducing friction as the eggshell is drawn along the hair shaft and that the final product was significantly (p < 0.05) more effective than several other marketed materials. In the usage study significantly (p = 0.01046) more louse eggs and nits were removed after treatment with the gel.DiscussionThe product developed through this study is the first with a demonstrable efficacy for loosening the grip of the louse egg fixative from hair. Consequently, until now, and despite the availability of effective pediculicidal treatments, dealing with the eggshells persisting after an infestation has been an onerous task for most households. This type of product can enable families to deal more easily with persistent eggshells and improve self-esteem in affected children.

Project description:Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease characterized by dysregulated lipid metabolism and chronic inflammation ultimately resulting in fibrosis. Untreated, NAFLD may progress to non-alcoholic steatohepatitis (NASH), cirrhosis and death. However, currently there are no FDA approved therapies that treat NAFLD/NASH. Thrombospondin-I (TSP-1) is a large glycoprotein in the extracellular matrix that regulates numerous cellular pathways including transforming growth factor beta 1 (TGF-β1) activation, angiogenesis, inflammation and cellular adhesion. Increased expression of TSP-1 has been reported in various liver diseases; however, its role in NAFLD/NASH is not well understood. We first examined TSP-1 modulation in hepatic stellate cell activation, a critical initiating step in hepatic fibrosis. Knockdown or inhibition of TSP-1 attenuated HSC activation measured by alpha smooth muscle actin (α-SMA) and Collagen I expression. To investigate the impact of TSP-1 modulation in context of NAFLD/NASH, we examined the effect of TSP-1 deficiency in the choline deficient L-amino acid defined high fat diet (CDAHFD) model of NASH in mice by assessing total body and liver weight, serum liver enzyme levels, serum lipid levels, liver steatosis, liver fibrosis and liver gene expression in wild type (WT) and TSP-1 null mice. CDAHFD fed mice, regardless of genotype, developed phenotypes of NASH, including significant increase in liver weight and liver enzymes, steatosis and fibrosis. However, in comparison to WT, CDAHFD-fed TSP-1 deficient mice were protected against numerous NASH phenotypes. TSP-1 null mice exhibited a decrease in serum lipid levels, inflammation markers and hepatic fibrosis. RNA-seq based transcriptomic profiles from the liver of CDAHFD fed mice determined that both WT and TSP-1 null mice exhibited similar gene expression signatures following CDAHFD, similar to biophysical and histological assessment comparison. Comparison of transcriptomic profiles based on genotype suggested that peroxisome proliferator activated receptor alpha (PPARα) pathway and amino acid metabolism pathways are differentially expressed in TSP-1 null mice. Activation of PPARα pathway was supported by observed decrease in serum lipid levels. Our findings provide important insights into the role of TSP-1 in context of NAFLD/NASH and TSP-1 may be a target of interest to develop anti-fibrotic therapeutics for NAFLD/NASH.

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

Publications

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

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