Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis

Zhang, Songwen; Wang, Juan; Liu, Qiangyuan; Harnish, Douglas C.

doi:10.1016/j.jhep.2009.03.025

Cited by 265 publications

(186 citation statements)

References 47 publications

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“…39) It was reported that feeding of MCD diets to mice increased the mRNA expression of MCP-1 in livers. 40) Our results also indicated that the mRNA expression of MCP-1 was increased in the liver of rats fed with MCD diets. Administration of the SCD-1 inhibitor attenuated the MCD diets-induced MCP-1 expression in liver of rats.…”

Section: -23)supporting

confidence: 66%

A Novel Inhibitor of Stearoyl-CoA Desaturase-1 Attenuates Hepatic Lipid Accumulation, Liver Injury and Inflammation in Model of Nonalcoholic Steatohepatitis

Kurikawa

Takagi

Wakimoto

et al. 2013

Biological & Pharmaceutical Bulletin

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Stearoyl-CoA desaturase-1 (SCD-1) catalyzes the biosynthesis of monounsaturated fatty acids, and their abnormality is possibly responsible for obesity, insulin resistance, hepatic steatosis and nonalcoholic steatohepatitis (NASH). A novel SCD-1 inhibitor, N-(2-hydroxy-2-phenylethyl)-6-[4-(2-methyl benzoyl) piperi din-1-yl]pyridazine-3-carboxamide, has been obtained. The compound inhibited liver SCD-1 activity and increased liver triglyceride accumulation in mice fed with non-fat, high-sucrose diets. In order to evaluate the effects of the SCD-1 inhibitor on NASH development, rats were fed with lipogenic methionine and choline-deficient (MCD) diets for 8 weeks. The SCD-1 inhibitor was administered once-daily at a dose of 30 or 100 mg/kg/d by oral gavage. Administration of a high dose of the SCD-1 inhibitor decreased triglyceride accumulation in the liver of NASH rats by 80%. Administration of a high dose of the SCD-1 inhibitor attenuated the increase of aspartate aminotransferase (AST) and alanine transaminase (ALT) by 86% and 78%, respectively. Hepatic steatosis, hepatocellular degeneration and inflammatory cell infiltration were histologically observed in the liver of NASH rats, and administration of the SCD-1 inhibitor ameliorated these crucial observations in NASH. In summary, an SCD-1 inhibitor ameliorated hepatic triglyceride accumulation, liver injury, hepatocellular degeneration and inflammation in experimental NASH models. These results suggest that SCD-1 maybe a promising target for the treatment of NASH.Key words stearoyl-CoA desaturase-1; steatohepatitis; methionine choline-deficient diet Nonalcoholic fatty liver disease (NAFLD), which is identified with excess lipid accumulation in the liver, is strongly associated with obesity, insulin resistance, hypertension, dyslipidemia and metabolic syndrome.1,2) Most NAFLD are in prognosis, although some of these progress to nonalcoholic steatohepatitis (NASH), which is defined as a histological observation of hepatocellular degeneration, inflammation and fibrosis in liver with steatosis. Finally, some NASH patients progress to liver cirrhosis and hepatocellular carcinomas, which are at the end-stage of liver disease. It is postulated that 3 to 6% of the population indicates NASH in the United States, and it is expected that the population of NASH patients will increase in the future.2) Therefore, there is a pressing need for developing a therapeutic drug to treat NASH. There are however, no therapeutic drugs approved for treating NASH patients, although some clinical pilot studies have indicated that some compounds, including insulin sensitizers, anti-dyslipidemic drugs, anti-hypertensive drugs, anti-obesity drugs and antioxidants, were effective for NASH/NAFLD. 3-9)Stearoyl-CoA desaturase (SCD) is an endoplasmic reticulum enzyme that catalyzes the biosynthesis of monounsaturated fatty acids (MUFAs) from saturated fatty acyl-CoAs. 10)SCD in conjunction with the reduced nicotinamide adenine dinucleotide phosphate (NADPH), the flavoprotein cytochrome b5 reducta...

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Section: -23)supporting

confidence: 66%

A Novel Inhibitor of Stearoyl-CoA Desaturase-1 Attenuates Hepatic Lipid Accumulation, Liver Injury and Inflammation in Model of Nonalcoholic Steatohepatitis

Kurikawa

Takagi

Wakimoto

et al. 2013

Biological & Pharmaceutical Bulletin

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“…Indeed, FXR defi ciency in LDLRdefi cient mice fed a high-fat diet leads to the development of NASH with infi ltration of infl ammatory cells and deposition of extracellular collagen ( 58 ). The administration of a synthetic FXR agonist reverses infl ammatory infi ltration and fi brosis in a FXR-dependent manner in mice fed a methionine-and choline-defi cient diet ( 59 ).…”

Section: Fxr and Lipid Metabolismmentioning

confidence: 99%

Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease

Porez

Prawitt²,

Gross³

et al. 2012

Journal of Lipid Research

255

173

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“…61 In alternate models of NASH, C57BL/6 mice fed a methionine and choline deficient diet and treated with the FXR agonist WAY-362450 for 4 weeks showed a decline in serum AST and ALT levels, improved liver histology and decreased inflammatory cell infiltration and fibrosis. 29 These studies indicate that FXR agonists may be useful for the treatment of NASH and related liver disorders by normalising carbohydrate, lipid and bile acid metabolism.…”

Section: Fxr Agonists In Nafld and Nashmentioning

confidence: 94%

Non-Alcoholic Fatty Liver Disease: The Effect of Bile Acids and Farnesoid X Receptor Agonists on Pathophysiology and Treatment

Q¹,

Bailey

Patel³

2015

Liver Res Open J

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Non-alcoholic fatty liver disease (NAFLD) is an emerging epidemic in light of its two predisposing factors, a surge in both obesity and diabetes rates with reports of between 70-80% of obese individuals in Western countries. The disease progression of NAFLD remains elusive but is generally attributed to insulin resistance, lipid metabolism dysfunction, altered immune response to name a few. Potential therapeutic strategies should target one or some of these pathological events in the liver, however currently no specific therapies for NAFLD exist. Thus novel therapeutic approaches to manage the chronic liver disease epidemic are becoming essential. In this review we discuss the evidence supporting the role of bile acid activated Farnesoid X Receptor (FXR) in promoting lipid oxidation, reducing inflammation and fibrosis in the liver. We also examine the potential of FXR agonists, as an attractive class of drugs for the safe and effective treatment of NAFLD.

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Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis

Cited by 265 publications

References 47 publications

A Novel Inhibitor of Stearoyl-CoA Desaturase-1 Attenuates Hepatic Lipid Accumulation, Liver Injury and Inflammation in Model of Nonalcoholic Steatohepatitis

A Novel Inhibitor of Stearoyl-CoA Desaturase-1 Attenuates Hepatic Lipid Accumulation, Liver Injury and Inflammation in Model of Nonalcoholic Steatohepatitis

Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease

Non-Alcoholic Fatty Liver Disease: The Effect of Bile Acids and Farnesoid X Receptor Agonists on Pathophysiology and Treatment

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