Co‐regulation of hepatic steatosis by ferritinophagy and unsaturated fatty acid supply. Issue 10 (21st July 2022)

• Record Type: Journal Article
• Authors: Li, Ning; Liao, Yilie; Huang, Haipeng; Fu, Suneng
• Is Part Of: Hepatology communications. Volume 6:Issue 10(2022)
• Page Start: 2640
• Page End: 2653
• Publication Date: 2022-07-21
• Subjects: Hepatology -- Periodicals; Liver -- Diseases -- Periodicals; Liver Diseases; Gastroenterology; Periodicals; Fulltext; Internet Resources; Periodicals; 616.36
• DOI: 10.1002/hep4.2040
• Languages: English
• ISSNs: 2471-254X

Abstract

Abstract: Both iron overload and iron deficiency have been reported in obesity and metabolic syndromes. Due to the presence of multiple intracellular iron pools and the dynamic nature of iron mobilization and use, the actual status and contribution of free and metabolically active iron toward metabolic syndrome remain to be established. The discovery of nuclear receptor coactivator 4 (NCOA4) as a ferritinophagy receptor provides an opening to address the connection between iron and metabolic diseases. This study aims to specifically dissect the role of hepatic ferritinophagy in lipid metabolism and hepatic steatosis. We conducted a series of Ncoa4 gain‐ and loss‐of‐function experiments to examine how ferritinophagy affects lipid metabolism through phenotypic and lipidomic analyses both in vitro and in vivo . We show that ferritinophagy is required to release iron from ferritin cages for biological use, and is induced by lipid loading in vitro and during the development of obesity in vivo . Ncoa4 knockdown impairs mitochondrial morphology and reduces palmitate‐induced lipid droplet formation in cultured cells and the development of hepatic steatosis in obese mice models. Importantly, the effect of Ncoa4 deficiency on mitochondrial morphology and lipid accumulation is specifically linked to lipidomic reductions in unsaturated fatty acid content in triglycerides and cardiolipins, and an external supply of unsaturated fatty acids reverses these phenotypes. Conclusion : This study shows that ferritinophagy‐derived iron supports fatty acid desaturation and the synthesis of unsaturated fatty acid–rich lipids to reduce lipotoxicity. However, the continuous activation of ferritinophagy contributes to the development of hepatic steatosis and liver damage in obesity. Abstract : Ferritinophagy not only controls the balance between stored and free iron but also regulates fatty acid desaturation and the synthesis of lipids with a high unsaturated fatty acid content, particularly triglycerides and cardiolipins.image