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

Cheng-hui Yan, Hai-Wei Liu, Xiao-xiang Tian, Jiayin Li, Ye Ding, Yi Li, Zhu Mei, Ming-Hui Zou and Ya-ling Han ()
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Cheng-hui Yan: General Hospital of Northern Theater Command
Hai-Wei Liu: General Hospital of Northern Theater Command
Xiao-xiang Tian: General Hospital of Northern Theater Command
Jiayin Li: General Hospital of Northern Theater Command
Ye Ding: Georgia State University
Yi Li: General Hospital of Northern Theater Command
Zhu Mei: General Hospital of Northern Theater Command
Ming-Hui Zou: Georgia State University
Ya-ling Han: General Hospital of Northern Theater Command

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-34996-x

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