Protective and Therapeutic Effects of Orlistat on Metabolic Syndrome and Oxidative Stress in High-Fat Diet-Induced Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) in Rats: Role on Nrf2 Activation

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.

Orlistat Mitigates Oxidative Stress-Linked Myocardial Damage via NF-κβ- and Caspase-Dependent Activities in Obese Rats

“…Orlistat treatments for 6 weeks to obese rats have shown to successfully deviate all these abnormalities. This might indicate that orlistat exhibits anti-obesity and anti-hyperlipidaemic activity, which is in line with other studies [ 19 , 20 ]. This could be due to its potent effect in inhibiting gastrointestinal lipase, thus preventing the absorption of dietary lipids at the intestinal level [ 21 ].…”

“…HFD was widely employed to explore the pathophysiology of obesity and its related complications in view of its characteristics that closely mimic human obesity. Scientific evidence has demonstrated that orlistat exhibits a wide range of pharmacological activities, for example, anti-obesity [ 9 ], anti-inflammatory [ 15 ], and anti-tumour [ 16 ] activities, as well as improved oxidative stress status in the brain, renal, testis, and liver organs [ 17 , 18 , 19 ]. In our earlier studies, orlistat that was given to HFD-fed rats for 6 and 12 weeks, had shown to significantly improve the oxidant–antioxidant status in the heart and aorta tissues [ 11 , 13 ].…”

Therapeutic Effects of Heterotrigona itama (Stingless Bee) Bee Bread in Improving Hepatic Lipid Metabolism through the Activation of the Keap1/Nrf2 Signaling Pathway in an Obese Rat Model

“…The present study demonstrated significant increases in the Lee obesity index and body weight gain in the obese group than those in the control group, which are consistent with our previously published reports [ 40 , 78 ]. Furthermore, excess energy or calorie intake following consumption of HFD led to an increased accumulation of lipids in the adipocytes, hence resulting in an increased Lee obesity index and body weight gain in this group, as reported by previous studies [ 33 , 37 ].…”

The protective effects of sulforaphane on high-fat diet-induced metabolic associated fatty liver disease in mice via mediating the FXR/LXRα pathway

“…A previous study proved that betaine significantly prevented HFD-induced MAFLD in ApoE −/− mice via the FGF10/AMPK signaling pathway. 35 As noted recently, ribaric acid could lower the expression of SREBP-1C, which is mediated by LXR, and therefore increased energy expenditure and reduced fat production, eventually reversing hepatic steatosis. 36 Curcumin improved HFDinduced MAFLD by inhibiting liver lipogenesis and regulating bile acid metabolism, which is associated with the Nrf2/FXR/ LXRα pathway.…”