Acetyl-CoA derived from hepatic mitochondrial fatty acid β-oxidation aggravates inflammation by enhancing p65 acetylation

Qiang Chen; Jianlong Du; Kun Cui; Wei Fang; Zengqi Zhao; Qiuchi Chen; Kangsen Mai; Qinghui Ai

doi:10.1016/j.isci.2021.103244

Acetyl-CoA derived from hepatic mitochondrial fatty acid β-oxidation aggravates inflammation by enhancing p65 acetylation

iScience. 2021 Oct 7;24(11):103244. doi: 10.1016/j.isci.2021.103244. eCollection 2021 Nov 19.

Authors

Qiang Chen¹, Jianlong Du¹, Kun Cui¹, Wei Fang¹, Zengqi Zhao¹, Qiuchi Chen¹, Kangsen Mai^{1

2}, Qinghui Ai^{1

2}

Affiliations

¹ Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) & Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, Qingdao, Shandong, 266003, People's Republic of China.
² Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, 1 Wenhai Road, Qingdao, Shandong, 266237, People's Republic of China.

Abstract

Acetylation coordinates many biological processes to ensure cells respond appropriately to nutrients. However, how acetylation regulates lipid surplus-induced inflammation remains poorly understood. Here, we found that a high-fat diet (HFD) enhanced mitochondrial fatty acid β-oxidation, which enhanced acetyl-CoA levels in the liver of the large yellow croaker. The HFD activated ACLY to govern the "citrate transport" to transfer acetyl-CoA from the mitochondria to the nucleus. Elevated acetyl-CoA activated CBP to increase p65 acetylation and then aggravated inflammation. SIRT1 was deactivated with a decline in NAD⁺/NADH, which further aggravated inflammation. Therefore, acetylation-dependent regulation of transcription factor activity is an adaptation to proinflammatory stimuli under nutrient stress, which was also confirmed in AML12 hepatocytes. In vitro octanoate stimulation further verified that acetyl-CoA derived from fatty acid β-oxidation mediated acetylation homeostasis in the nucleus. The broad therapeutic prospects of intermediate metabolites and acetyltransferases/deacetylases might provide critical insights for the treatment of metabolic diseases in vertebrates.

Keywords: Cellular physiology; Immunology; Pathophysiology.