Abstract
Previous studies have shown that the CB1 receptor antagonist reverses steatohepatitis and its related features of metabolic syndrome, such as obesity and type 2 diabetes. However, the beneficial effects of CB1 receptor blockade on hepatic steatosis and inflammation have not been investigated independently of its effects on body weight and glycemic control. At 32 weeks of age, OLETF rats were administered with rimonabant (10 mg·kg−1·day−1) by oral gavage for 6 weeks. No significant changes in body weight, OGTT, and serum glucose were observed in spite of rimonabant-decreased food intake. Moreover, there was a significant difference between initial and final body weight, regardless of rimonabant administration, indicating that OLETF rats were severely diabetic rats. Rimonabant administration significantly decreased serum liver enzyme levels such as ALT and AST, hepatic fat accumulation, lipid peroxidation, and cell death as demonstrated by the number of TUNEL-positive cells in severely uncontrolled diabetic OLETF rats. Significant decreases in hepatic gene expression of proinflammatory cytokines (CD11b, F4/80, MCP1, and TNFα), negative inflammatory mediators (SOCS1 and SOCS3), and fibrosis-related proteins (TGFβ, collagen 1, and TIMP1) were found in rimonabant-treated OLETF rats. Six-week administration of rimonabant significantly upregulated mRNA levels of CPT1α and PPARα related to β-oxidation. Moreover, significant increases in Nrf2 gene expression and its downstream genes, NQO1, GSAT, HO-1, and TXNRD1 along with increased AMPK phosphorylation were noted in uncontrolled diabetic rats treated with rimonabant. The observed potent inhibitory effects of CB1 receptor blockade on hepatic fat infiltration and cellular death in severely uncontrolled diabetic rats indicate that CB1 receptor is a possible therapeutic target. Increased Nrf2 and AMPK phosphorylation may play a role in the mechanism of rimonabant action.
Highlights
Nonalcoholic fatty liver disease (NAFLD) encompasses a wide range of diseases from simple steatosis to hepatic inflammation, hepatocellular ballooning, hepatic injury and fibrosis, and cellular death, all of which are referred to as nonalcoholic steatohepatitis (NASH)
We evaluated whether rimonabant significantly reduced hepatic TG levels by regulating genes involved in fatty acid oxidation. mRNA levels of carnitine palmitoyltransferase 1α (CPT1α) and peroxisome proliferator-activated receptor α (PPARα), which are involved in β-oxidation, were significantly upregulated by 6 weeks of rimonabant administration in severely uncontrolled diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats (Fig 5A)
Rimonabant has been withdrawn from the market because of an increase in psychiatric disorders [36], it is still important to determine the role of cannabinoid 1 (CB1) receptor in the pathogenesis of hepatic steatosis and the progression of NASH, and to investigate its underlying mechanism, especially independently of CB1-receptor-mediated weight loss and glycemic control
Summary
Nonalcoholic fatty liver disease (NAFLD) encompasses a wide range of diseases from simple steatosis (aberrant hepatic lipid accumulation) to hepatic inflammation, hepatocellular ballooning, hepatic injury and fibrosis, and cellular death, all of which are referred to as nonalcoholic steatohepatitis (NASH). NASH results in cirrhosis and hepatocellular carcinoma [1, 2]. Advanced fibrosis has been reported in 5–7% of asymptomatic individuals with type 2 diabetes [3, 4]. Individuals with severe diabetes are more likely to have more severe NAFLD with hepatic inflammation and fibrosis [5, 6]. The pathogenesis of NASH is not fully understood. There is no available pharmacotherapy to fully reverse and prevent NASH. It is important to explore possible therapeutic strategies for NASH
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