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

Abstract

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...

Hepatotoxic Effects of Fenofibrate in Spontaneously Hypertensive Rats Expressing Human C-Reactive Protein

“…It can be therefore expected that the effect of fenofibrate on ScdI is mediated by PPARα activation. It has been demonstrated in a rat model of non-alcoholic steatohepatitis (NASH) (rats fed a methionine and choline-deficient diet) that pharmacological inhibition of Scd1 is associated with reduced hepatic steatosis, lower ALT and AST levels, and amelioration of hepatocellular degeneration and inflammation (Kurikawa et al 2013). These findings are in agreement with the results of the current study, where increased expression of Scd1 was associated with hepatotoxic effects.…”

Overfeeding Polyunsaturated and Saturated Fat Causes Distinct Effects on Liver and Visceral Fat Accumulation in Humans

“…Hepatic activity of the lipogenic enzyme SCD-1 may be elevated in steatosis (26). Also, SCD-1-deficient mice were protected against hepatic lipogenesis, whereas SCD-1 inhibitors markedly reduced hepatic triglyceride accumulation (35). In humans, a strong association between the change in liver fat and the change in hepatic SCD-1 index was reported in weight-stable subjects (22), a finding currently confirmed during hypercaloric conditions.…”

Characterization of hepatic lipid profiles in a mouse model with nonalcoholic steatohepatitis and subsequent fibrosis

“…In humans with NAFLD, free fatty acids, which undergo esterification into triglycerides, circulate at higher levels in the blood, leading to fat accumulation in the liver 8 9 . Another report has demonstrated that stearoyl-CoA desaturase (SCD1), an enzyme that synthesizes monounsaturated fatty acids from saturated fatty acids, plays an important role in hepatic lipid accumulation and NASH progression 10 . Moreover, depletion of the palmitate elongase, Elovl6, attenuated NASH progression in mice, and expression of Elovl6 was positively correlated with severity of steatosis and liver injury in human NASH patients 11 .…”