10-Hydroxy-2-decenoic acid attenuates nonalcoholic fatty liver disease by activating AMPK-α signaling pathway

[Display omitted] Nonalcoholic fatty liver disease (NAFLD) originates from metabolic dysfunctions, is one of the most commonly encountered liver disorders worldwide, characterized by ectopic lipid deposition within hepatocytes, accompanied by hepatocellular injury and necroinflammation. Currently, NAFLD has very few treatment options. Purified from royal jelly, 10-hydroxy-2-decenoic acid (10-HDA) is the primary bioactive ingredient with a series of beneficial effects against various metabolic diseases. Herein, we investigated the effects of 10-HDA in methionine and choline deficiency (MCD) diet induced NAFLD model and free fatty acids (FFAs) induced lipid-laden hepatocyte model and explored the underlying mechanisms. In the mice fed with MCD diet, 10-HDA treatment significantly reduced hepatic steatosis, hepatocellular injury, apoptosis, inflammatory response and fibrosis. In vitro, 10-HDA treatment reduced lipid accumulation and apoptosis in hepatocytes induced by FFAs. Mechanistically, 10-HDA therapy restored AMPK-α phosphorylation, leading to the phosphorylation and inactivation acetyl-CoA carboxylase (ACC). Consequently, this increased the expression of carnitine palmitoyl transferase 1α(CPT1α), and peroxisome proliferators-activated receptors α (PPARα), and lowered the expression of cleavage forms of sterol regulatory element binding protein-1 (SREBP-1) and fatty acid synthetase (FASN). Furthermore, pretreating the cells with the AMPK-α inhibitor, compound C, greatly eliminated these beneficial effects of 10-HDA. Additionally, molecular docking analysis indicated that 10-HDA bound the domain of AMPK-α1 subunit. Based on these findings, 10-HDA suppresses hepatic lipogenesis via AMPK-α-dependent suppression of the ACC pathway, thus inhibiting hepatocellular injury, apoptosis, inflammatory response and fibrosis. 10-HDA may represent a promising candidate drug for the treatment of NAFLD.