Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is an excessive buildup of liver lipids closely associated with various kinds of undesirable metabolic effects and oxidative stress. We aimed to investigate the protective and therapeutic effects of orlistat on metabolic syndrome and oxidative stress parameters in high-fat diet (HFD) induced-MAFLD rats. Twenty-four male Sprague-Dawley rats were randomly divided into four groups (n = 6/group), i.e., Normal control (N), HFD, HFD + orlistat (HFD + O) (10 mg/kg/day administered concomitantly for 12 weeks as a protective model), and obese+orlistat (OB + O) (10 mg/kg/day administered 6 weeks after induction of obesity as a therapeutic model) groups. After 12 weeks, the HFD group had significantly increased Lee obesity index, serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total cholesterol, triglyceride, low-density lipoprotein levels, liver total cholesterol and triglyceride levels, insulin resistance and non-alcoholic steatohepatitis (NASH) together with decreased serum high-density lipoprotein level. Additionally, the HFD group also showed increased Nrf2 translocation to the nucleus with high Keap1 expression and increased liver oxidative stress parameters. Orlistat significantly improved all these alterations in HFD rats. We demonstrated that orlistat might have protective and therapeutic effects against HFD-induced MAFLD rats by its activation on Nrf2 signaling pathway, which subsequently improved metabolic syndrome and oxidative stress parameters.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is recognized as an abnormal accumulation of triglycerides (TGs) in the hepatocytes and comprises a spectrum of histological findings that range from simple steatosis to non-alcoholic steatohepatitis (NASH) [2], advanced fibrosis, cirrhosis, hepatocellular carcinoma, and liver-related mortality [3,4]
Rats in the high-fat diet (HFD) group demonstrated significant increased Lee obesity index as well as body weight gain compared to rats in the N group
Increased oxidative stress level initiates the activation of serine-threonine kinases activities such as c-Jun N-terminal kinase, which results in phosphorylation of serine residues in the insulin receptor substrate (IRS) protein, which in turn inhibits the effect of insulin signaling pathway [81]. This is in line with our findings in which significant increases in the oxidative stress markers such as thiobarbituric acid reactive substances (TBARS), nitric oxide (NO), and protein carbonyl (PCO) levels were shown in the HFD group compared to the N group, suggesting the presence of oxidative stress that may play an essential role to the insulin resistance in HFD group
Summary
Non-alcoholic fatty liver disease (NAFLD) is linked with obesity and imbalance dietary intake such as excessive intake of high-fat diet (HFD). Many studies have been reported the relation between NAFLD and the main features of metabolic syndrome [5,6], which include obesity [7,8], hyperglycemia [9], hyperlipidemia [10,11], hypertension [12,13], insulin resistance [14,15], and a proinflammatory state [16]. This condition has been newly re-named as metabolic dysfunctionassociated fatty liver disease (MAFLD) [17,18] and the new acronym MAFLD is used to replace the older term NAFLD throughout this study. The latest studies have come out with evidence which support the idea that increased oxidative stress could be one of the key players in metabolic syndrome, which manifests many life-threating diseases including atherosclerosis [21], hypertension [22], and type 2 diabetes [23]
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