New drugs for non‐alcoholic steatohepatitis

Cardoso, Abel Silveira; Figueiredo-Mendes, C.; Villela-Nogueira, Cristiane Alves; Sanyal, Arun J.

doi:10.1111/liv.14354

Cited by 24 publications

(16 citation statements)

References 19 publications

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“…Notably, the gene enrichment analysis also identified comprehensive changes in several ECM genes regulating hepatic collagen formation and turnover, supporting biochemical and histological evidence of extensive ECM remodeling activity in GAN DIO NASH mice and NASH patients. To obtain further resolution of hepatic transcriptome regulations in GAN DIO-NASH mice and NASH patients, RNA sequencing data were probed for genes encoding various protein targets exploited for the treatment of NASH, including regulators of hepatic lipid handling, adipogenesis, peripheral insulin sensitivity, immune cell function and ECM formation [7,31,32]. Compared to NASH patients, GAN DIO-NASH mice showed more widespread regulations within the defined gene set.…”

Section: Discussionmentioning

confidence: 99%

Human translatability of the GAN diet-induced obese mouse model of non-alcoholic steatohepatitis

et al. 2020

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Background: Animal models of non-alcoholic steatohepatitis (NASH) are important tools in preclinical research and drug discovery. Gubra-Amylin NASH (GAN) diet-induced obese (DIO) mice represent a model of fibrosing NASH. The present study directly assessed the clinical translatability of the model by head-to-head comparison of liver biopsy histological and transcriptome changes in GAN DIO-NASH mouse and human NASH patients. Methods: C57Bl/6 J mice were fed chow or the GAN diet rich in saturated fat (40%), fructose (22%) and cholesterol (2%) for ≥38 weeks. Metabolic parameters as well as plasma and liver biomarkers were assessed. Liver biopsy histology and transcriptome signatures were compared to samples from human lean individuals and patients diagnosed with NASH. Results: Liver lesions in GAN DIO-NASH mice showed similar morphological characteristics compared to the NASH patient validation set, including macrosteatosis, lobular inflammation, hepatocyte ballooning degeneration and periportal/perisinusoidal fibrosis. Histomorphometric analysis indicated comparable increases in markers of hepatic lipid accumulation, inflammation and collagen deposition in GAN DIO-NASH mice and NASH patient samples. Liver biopsies from GAN DIO-NASH mice and NASH patients showed comparable dynamics in several gene expression pathways involved in NASH pathogenesis. Consistent with the clinical features of NASH, GAN DIO-NASH mice demonstrated key components of the metabolic syndrome, including obesity and impaired glucose tolerance. Conclusions: The GAN DIO-NASH mouse model demonstrates good clinical translatability with respect to the histopathological, transcriptional and metabolic aspects of the human disease, highlighting the suitability of the GAN DIO-NASH mouse model for identifying therapeutic targets and characterizing novel drug therapies for NASH.

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Section: Discussionmentioning

confidence: 99%

Human translatability of the GAN diet-induced obese mouse model of non-alcoholic steatohepatitis

et al. 2020

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“…However, an accelerated approval has not been granted by the FDA as the observed efficacy of OCA potentially does not outweigh the potential risks. Many other compounds are in clinical development (17) but most of these have not yet reached phase 3. The drug candidates can on a top level be divided into three main categories 1) metabolic compounds with effect on steatosis (PPAR agonists, ACC inhibitors, Ketohexokinase inhibitors, DGAT2 inhibitors, SCD1 inhibitors, SGTL2 inhibitors, GLP-1 receptor agonist or derivates thereof, THRb agonists, FGF19, and FGF21 analogues etc.…”

Section: Treatment For Nashmentioning

confidence: 99%

“…Reversal of hepatic steatosis is of crucial importance to improve liver health and several pharmacological approaches to lower DNL or to increase lipid oxidation are in development (17). FGF19 and FGF21 both depend on KLB expression in the CNS to lower hepatic steatosis (91).…”

Section: Anti-steatotic Effectsmentioning

confidence: 99%

FGF19 and FGF21 for the Treatment of NASH—Two Sides of the Same Coin? Differential and Overlapping Effects of FGF19 and FGF21 From Mice to Human

Henriksson

Andersen

2020

Front. Endocrinol.

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FGF19 and FGF21 analogues are currently in clinical development for the potential treatment of NASH. In Phase 2 clinical trials analogues of FGF19 and FGF21 decrease hepatic steatosis with up to 70% (MRI-PDFF) after 12 weeks and as early as 12–16 weeks of treatment an improvement in NASH resolution and fibrosis has been observed. Therefore, this class of compounds is currently of great interest in the field of NASH. FGF19 and FGF21 belong to the endocrine FGF19 subfamily and both require the co-receptor beta-klotho for binding and signalling through the FGF receptors. FGF19 is expressed in the ileal enterocytes and is released into the enterohepatic circulation in response to bile acids stimuli and in the liver FGF19 inhibits hepatic bile acids synthesis by transcriptional regulation of Cyp7A1, which is the rate limiting enzyme. FGF21 is, on the other hand, highly expressed in the liver and is released in response to high glucose, high free-fatty acids and low amino-acid supply and regulates energy, glucose and lipid homeostasis by actions in the CNS and in the adipose tissue. FGF19 and FGF21 are differentially expressed, have distinct target tissues and separate physiological functions. It is therefore of peculiar interest to understand why treatment with both FGF19 and FGF21 analogues have strong beneficial effects on NASH parameters in mice and human and whether the mode of action is overlapping This review will highlight the physiological and pharmacological effects of FGF19 and FGF21. The potential mode of action behind the anti-steatotic, anti-inflammatory and anti-fibrotic effects of FGF19 and FGF21 will be discussed. Finally, development of drugs is always a risk benefit analysis and the human relevance of adverse effects observed in pre-clinical species as well as findings in humans will be discussed. The aim is to provide a comprehensive overview of the current understanding of this drug class for the potential treatment of NASH.

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“…Recent clinical evidence suggests that significant fibrosis is the most critical histological feature associated with overall mortality, liver transplantation, and liver-related events in patients with NASH [5]. The several pharmacological strategies which have been proposed for the treatment of NASH-based fibrosis will not be ready for clinical use in near future [6,7]. NASH pathogenesis has been recognized to be based on "multiple parallel hits" [4].…”

Section: Introductionmentioning

confidence: 99%

Bile Acid Sequestrant, Sevelamer Ameliorates Hepatic Fibrosis with Reduced Overload of Endogenous Lipopolysaccharide in Experimental Nonalcoholic Steatohepatitis

et al. 2020

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Despite the use of various pharmacotherapeutic strategies, fibrosis due to nonalcoholic steatohepatitis (NASH) remains an unsatisfied clinical issue. We investigated the effect of sevelamer, a hydrophilic bile acid sequestrant, on hepatic fibrosis in a murine NASH model. Male C57BL/6J mice were fed a choline-deficient, L-amino acid-defined, high-fat (CDHF) diet for 12 weeks with or without orally administered sevelamer hydrochloride (2% per diet weight). Histological and biochemical analyses revealed that sevelamer prevented hepatic steatosis, macrophage infiltration, and pericellular fibrosis in CDHF-fed mice. Sevelamer reduced the portal levels of total bile acid and inhibited both hepatic and intestinal farnesoid X receptor activation. Gut microbiome analysis demonstrated that sevelamer improved a lower α-diversity and prevented decreases in Lactobacillaceae and Clostridiaceae as well as increases in Desulfovibrionaceae and Enterobacteriaceae in the CDHF-fed mice. Additionally, sevelamer bound to lipopolysaccharide (LPS) in the intestinal lumen and promoted its fecal excretion. Consequently, the sevelamer treatment restored the tight intestinal junction proteins and reduced the portal LPS levels, leading to the suppression of hepatic toll-like receptor 4 signaling pathway. Furthermore, sevelamer inhibited the LPS-mediated induction of fibrogenic activity in human hepatic stellate cells in vitro. Collectively, sevelamer inhibited the development of murine steatohepatitis by reducing hepatic LPS overload.

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New drugs for non‐alcoholic steatohepatitis

Cited by 24 publications

References 19 publications

Human translatability of the GAN diet-induced obese mouse model of non-alcoholic steatohepatitis

Human translatability of the GAN diet-induced obese mouse model of non-alcoholic steatohepatitis

FGF19 and FGF21 for the Treatment of NASH—Two Sides of the Same Coin? Differential and Overlapping Effects of FGF19 and FGF21 From Mice to Human

Bile Acid Sequestrant, Sevelamer Ameliorates Hepatic Fibrosis with Reduced Overload of Endogenous Lipopolysaccharide in Experimental Nonalcoholic Steatohepatitis

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