Rhinacanthin C Ameliorates Insulin Resistance and Lipid Accumulation in NAFLD Mice via the AMPK/SIRT1 and SREBP-1c/FAS/ACC Signaling Pathways

Abstract

Rhinacanthin C (RC) is a naphthoquinone ester with an anti-inflammatory activity extracted from Rhinacanthus nasutus (L.) Kurz (Rn). It has been proven to improve hyperglycemia and hyperlipidemia, but the prevention and mechanism of RC in nonalcoholic fatty liver disease (NAFLD) are not clear. In the current study, we first extracted RC from Rn using ethyl acetate and identified it by HPLC, MS, and NMR. At the same time, molecular docking analysis of RC with AMPK and SREBP-1c was performed using AutoDock software. In addition, the mouse model of NAFLD was induced by a high-fat diet in vivo, and low, medium, and high concentrations of RC were used for intervention. The results showed that RC significantly reduced the body mass and liver body coefficient of NAFLD mice, inhibited liver inflammation and fat accumulation, and improved insulin resistance. Further studies showed that RC significantly reduced the levels of serum leptin and resistin, upregulated the expression levels of adiponectin and adiponectin receptor in the liver, and inhibited the expression levels of MCP-1, TNF-α, and IL-6. In terms of mechanism, RC upregulates the expression of p-AMPK and SIRT1 and downregulates the expression of p-p65, SREBP-1c, Fas, Acc-α, PPAR-γ, and SCD1. These studies suggest that RC improves insulin resistance and lipid accumulation in NAFLD by activating the AMPK/SIRT1 and SREBP-1c/Fas/ACC pathways, respectively.

Physalis alkekengi L. Calyx Extract Alleviates Glycolipid Metabolic Disturbance and Inflammation by Modulating Gut Microbiota, Fecal Metabolites, and Glycolipid Metabolism Gene Expression in Obese Mice

“…SREBP-1c mainly regulates genes related to triglyceride and fatty acid synthesis, such as ACC and SCD1 [49]. Recent studies have shown that SREBP-1c can also inhibit the transcription of insulin receptor substrate-2 (IRS-2), thereby exacerbating insulin resistance; this suggested that it might have a negative regulatory effect on insulin signaling [50,51]. ChREBPα is a transcription factor in the glucose signaling pathway, which plays an important role in regulating glucose metabolism [52], fat metabolism, and fat deposition in mammals [53].…”

The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease—The Transition from an Adipocentric to Liver-Centric Approach

“…Targeting ER and UPR signaling in insulin resistance and T2DM might be a viable solution and therapeutic approach. It has been shown that AMPK activation inhibited ER stress-induced SREBP-1 and thus prevented the development of lipid-induced ER stress [44,148]. Another study using the plant sterol ester of α-linolenic acid improved MASLD by alleviating ER stress-triggered apoptosis through AMPK activation [149].…”