Methyl Brevifolincarboxylate Attenuates Free Fatty Acid-Induced Lipid Metabolism and Inflammation in Hepatocytes through AMPK/NF-κB Signaling Pathway

Abstract

The prevalence of non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver diseases worldwide. This study examined the potential protective effects of a naturally occurring polyphenolic compound, methyl brevifolincarboxylate (MBC) on fatty liver injury in vitro. The results showed that MBC at its non-cytotoxic concentrations, reduced lipid droplet accumulation and triglyceride (TG) levels in the oleic acid (OA)-treated human hepatocarcinoma cell line, SK-HEP-1 and murine primary hepatocytes. In OA-treated SK-HEP-1 cells and primary murine hepatocytes, MBC attenuated the mRNA expression levels of the de novo lipogenesis molecules, acetyl-coenzyme A carboxylase (Acc1), fatty acid synthase (Fasn) and sterol regulatory element binding protein 1c (Srebp1c). MBC promoted the lipid oxidation factor peroxisome proliferator activated receptor-α (Pparα), and its target genes, carnitine palmitoyl transferase 1 (Cpt1) and acyl-coenzyme A oxidase 1 (Acox1) in both the SK-HEP-1 cells and primary murine hepatocytes. The mRNA results were further supported by the attenuated protein expression of lipogenesis and lipid oxidation molecules in OA-treated SK-HEP-1 cells. The MBC increased the expression of AMP activated protein kinase (AMPK) phosphorylation. On the other hand, MBC treatment dampened the inflammatory mediator’s, tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), IL-8, and IL-1β secretion, and nuclear factor (NF)-κB expression (mRNA and protein) through reduced reactive oxygen species production in OA-treated SK-HEP-1 cells. Taken together, our results demonstrated that MBC possessed potential protective effects against NAFLD in vitro by amelioration of lipid metabolism and inflammatory markers through the AMPK/NF-κB signaling pathway.

l-carnitine alleviates synovitis in knee osteoarthritis by regulating lipid accumulation and mitochondrial function through the AMPK-ACC-CPT1 signaling pathway

“…2 b). Numerous studies have shown a crucial role for the AMPK/CPT1 pathway in inflammatory diseases [ 31 ]. In this study, we hypothesized that l -carnitine induced CPT1 upregulation mediated by AMPK in the LPS-stimulated FLS model.…”

Recent evaluation about inflammatory mechanisms in nonalcoholic fatty liver disease

“…Free fatty acids derived from adipose tissue breakdown serve as natural nuclear receptor ligands and play a major role in the regulation of NASH-related lipid metabolism and inflammation ( Yadati et al, 2021 ). Polyunsaturated fatty acids and their derivatives could activate peroxisome proliferator-activated receptor-α (PPARα), which could induce the expressions of genes involved in fatty acid oxidation and insulin sensitivity, and downregulate nuclear factor κB (NF-κB) level ( Geethangili et al, 2021 ; López-Salazar et al, 2021 ). However, in a mouse model of NASH, a diet fed polyunsaturated fatty acids activates PPARα signaling and inhibits hepatic de novo fat synthesis, but does not prevent steatohepatitis ( Ishida et al, 2021 ), which is likely to high levels of hepatic lipid peroxidation in this model abolished the protective effect of PPARα activation and resulted in lipotoxic hepatocyte injury and inflammatory cells recruitment.…”

Diet and Gut Microbiota Interaction-Derived Metabolites and Intrahepatic Immune Response in NAFLD Development and Treatment

“…In addition, they can decrease both serum and liver proinflammatory cytokines that contribute to the fatty liver [ 104 ]. Treatment with methyl brevifolincarboxylate, a natural polyphenolic compound, reduced lipid metabolism and inflammatory markers, such as TNF-α, IL-6, and IL-1β, via modulating 5′ adenosine monophosphate-activated protein kinase (AMPK)/NF-κB signaling pathway [ 105 ]. However, clinical studies are still needed to confirm the function of polyphenols.…”