Swietenine Alleviates Nonalcoholic Fatty Liver Disease in Diabetic Mice via Lipogenesis Inhibition and Antioxidant Mechanisms

Abstract

Our previous studies have reported the effect of swietenine (a major bioactive component of Swietenia macrophylla seeds) in reversing and potentiating the effect of metformin in hyperglycemia and hyperlipidaemia in diabetic rats. Moreover, we reported that the anti-inflammatory effect of swietenine is mediated via the activation of nuclear factor erythroid 2-related factor 2 (Nrf2). This study evaluated the effect of swietenine and its mechanisms in nonalcoholic fatty liver disease (NAFLD) in high-fat diet/streptozotocin-induced diabetic mice. The effect was assessed by determining blood biochemical parameters (glucose, cholesterol, triglycerides, alanine transaminase (ALT), asparate transaminase (AST), alkaline phosphatase (ALP), glutathione (GSH), total antioxidant capacity (TAC), and malondialdehyde (MDA)) and liver biochemical parameters (liver index, cholesterol, and triglycerides). Hepatic lipid accumulation (initial causative factor in NAFLD) was determined by oil-O-red staining. Gene expression (qPCR) and immunohistochemical studies were performed to elucidate the mechanism of swietenine’s effect in NAFLD. The critical regulators (genes and proteins) involved in lipogenesis (ACLY, ACC1, FASN, SREBP1c, and ChREBPβ) and oxidative stress (Nrf2, NQO-1 and HO-1) pathways were determined. In mice fed with a high-fat diet followed by streptozotocin injection, the liver cholesterol, triglycerides, and lipids were elevated. These increases were reversed by the oral administration of swietenine, 80 mg/kg body weight, on alternate days for eight weeks. Gene expression and immunohistochemical studies showed that swietenine reversed the elevated levels of crucial enzymes of lipogenesis (ACLY, ACC1 and FASN) and their master transcription factors (SREBP1c and ChREBPβ). Furthermore, swietenine activated the Nrf2 antioxidant defense mechanism, as evidenced by the upregulated levels of Nrf2, NQO-1, and HO-1. It is concluded that swietenine shows beneficial effects in diabetes-induced NAFLD via inhibiting lipogenesis and activating the Nrf2 pathway.

Exploring the Regulatory Effect of Tegillarca granosa Polysaccharide on High‐Fat Diet‐Induced Non‐Alcoholic Fatty Liver Disease in Mice Based on Intestinal Flora

“…In addition, SREBP‐1c acts as a crucial transcription factor involved in adipose differentiation and adipogenesis in the liver, playing a vital role in the pathogenesis of NAFLD. [ 38 ] As a downstream marker molecule, FAS provides a nonesterified fatty acid substrate for TG, enhancing fatty acid synthesis and TG accumulation. [ 39 ] AMPKα1 directly regulates the phosphorylation of adipogenic SREBP‐1c and inhibits its activity, regulating the expression of FAS and reducing adipogenesis.…”

A Systematic Review on the Hypoglycemic Potentials of Mahogany (Swietenia spp.) Seeds as Antioxidants in the Management of Gestational Diabetes Mellitus

“…Whereas in the immunohistochemistry study, the levels of Nrf2, NQO-1, and HO-1 were 2.53 ± 0.03, 1.59 ± 0.01, and 1.82 ± 0.02, respectively. 17 After 21 days of treatment with S. macrophylla seed extract, the average glucose and MDA levels in each of the following treatment groups: (DM + glibenclamide, DM + mahogany seed extract 10 mg/kg BW, DM + mahogany seed extract 20 mg/kg BW, and DM + mahogany seed extract 40 mg/kg BW) were significantly decrease over time. On day 0, the average serum MDA level in all groups increases by greater than 2 nmol/mL, except in the normal control group.…”

Natural product Swietenine improve the progression of diabetic nephropathy by inhibiting ferroptosis through activation of the Akt/GSK-3β/Nrf2 signaling pathway

“…Swi, a natural product, has been proved to be one of the few medicinal plants with anti diabetes effect [44] . Swi's recent research includes the treatment of various diseases caused by in ammation and oxidative stress [45] . According to reports, Swi can be accessed through NF-κB/NLRP3/Caspase-1 signaling pathway reduces in ammation and oxidative stress and improves DN [46] .…”