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
Affiliations
Qiang Chen
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
Jianlong Du
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
Kun Cui
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
Wei Fang
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
Zengqi Zhao
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
Qiuchi Chen
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
Kangsen Mai
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; 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
Qinghui Ai
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; 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; Corresponding author
Summary: 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.
