AMPKα2 controls the anti-atherosclerotic effects of fish oils by modulating the SUMOylation of GPR120

• Published in: Nature communications Vol. 13; no. 1; p. 7721
• Main Authors: Yan, Cheng-hui, Liu, Hai-Wei, Tian, Xiao-xiang, Li, Jiayin, Ding, Ye, Li, Yi, Mei, Zhu, Zou, Ming-Hui, Han, Ya-ling
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.12.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/21; 13/89; 38; 38/77; 42; 45; 692/4019; 692/699/75; 82/51; 82/80; AMP-activated protein kinase; AMP-Activated Protein Kinases - metabolism; Animals; Aorta; Arrestin; Arteries; Arteriosclerosis; Atherosclerosis; Atherosclerosis - drug therapy; Atherosclerosis - genetics; Atherosclerosis - pathology; c-Myc protein; Cardiovascular disease; Cardiovascular diseases; Cardiovascular Diseases - pathology; Fatty acids; Fish oils; Fish Oils - pharmacology; Glucose metabolism; Health risks; Humanities and Social Sciences; Humans; In vivo methods and tests; Inactivation; Inflammation; Internalization; Kinases; Lipid metabolism; Lipids; Localization; Mice; multidisciplinary; Muscles; Myc protein; Myocytes, Smooth Muscle - metabolism; Populations; Post-translation; Receptors; Risk management; Science; Science (multidisciplinary); Smooth muscle; Subgroups; SUMO protein; Sumoylation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34996-x

Consuming fish oils (FO) is linked to reduced risk of cardiovascular disease in certain populations. However, FO failed to exhibit therapeutic effects in some patients with cardiovascular disease. This study aimed to determine the possible reasons for the inconsistent effects of FO. AMP-activated protein kinase (AMPK) α2 is an important energy metabolic sensor, which was reported to involve in FO mediated regulation of lipid and glucose metabolism. In an in vivo study, FO administration significantly reduced the aortic lesions and inflammation in the Ldlr −/− mouse model of atherosclerosis, but not in Ldlr −/− / Prkaa2 −/− and Ldlr −/− / Prkaa2 −/−Sm22Cre mice. Mechanistically, inactivation of AMPKα2 increased the SUMOylation of the fatty acid receptor GPR120 to block FO-induced internalization and binding to β-arrestin. In contrast, activation of AMPKα2 can phosphorylate the C-MYC at Serine 67 to inhibit its trans-localization into the nuclei and transcription of SUMO-conjugating E2 enzyme UBC9 and SUMO2/3 in vascular smooth muscle cells (VSMCs), which result in GPR120 SUMOylation. In human arteries, AMPKα2 levels were inversely correlated with UBC9 expression. In a cohort of patients with atherosclerosis, FO concentrations did not correlate with atherosclerotic severity, however, in a subgroup analysis a negative correlation between FO concentrations and atherosclerotic severity was found in patients with higher AMPKα2 levels. These data indicate that AMPKα2 is required for the anti-inflammatory and anti-atherosclerotic effects of FO. Consuming fish oil is linked to reduced risk of cardiovascular disease in some populations, but the effects are not consistent across studies. Here the authors report that smooth muscle cell AMPKα2 is required for the protective effects of fish oil on atherosclerosis in mice, and acts via post-translational regulation of the fatty acid receptor GPR120.