Essential lipid autacoids rewire mitochondrial energy efficiency in metabolic dysfunction-associated fatty liver disease

• Published in: Hepatology (Baltimore, Md.) Vol. 77; no. 4; pp. 1303 - n/a
• Main Authors: López-Vicario, Cristina, Sebastián, David, Casulleras, Mireia, Duran-Güell, Marta, Flores-Costa, Roger, Aguilar, Ferran, Lozano, Juan José, Zhang, Ingrid W, Titos, Esther, Kang, Jing X, Zorzano, Antonio, Arita, Makoto, Clària, Joan
• Format: Journal Article
• Language: English
• Published: United States 01.04.2023
• Subjects: Animals; Conservation of Energy Resources; Fatty Acids - metabolism; Fatty Acids, Omega-3 - chemistry; Fatty Acids, Omega-3 - metabolism; Fatty Acids, Omega-3 - pharmacology; Fatty Acids, Omega-6 - chemistry; Fatty Acids, Omega-6 - metabolism; Fatty Acids, Omega-6 - pharmacology; Liver - metabolism; Mice; Mice, Transgenic; Mitochondria - metabolism; Non-alcoholic Fatty Liver Disease - metabolism
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.32647

Injury to hepatocyte mitochondria is common in metabolic dysfunction-associated fatty liver disease. Here, we investigated whether changes in the content of essential fatty acid-derived lipid autacoids affect hepatocyte mitochondrial bioenergetics and metabolic efficiency. The study was performed in transgenic mice for the fat-1 gene, which allows the endogenous replacement of the membrane omega-6-polyunsaturated fatty acid (PUFA) composition by omega-3-PUFA. Transmission electron microscopy revealed that hepatocyte mitochondria of fat-1 mice had more abundant intact cristae and higher mitochondrial aspect ratio. Fat-1 mice had increased expression of oxidative phosphorylation complexes I and II and translocases of both inner (translocase of inner mitochondrial membrane 44) and outer (translocase of the outer membrane 20) mitochondrial membranes. Fat-1 mice also showed increased mitofusin-2 and reduced dynamin-like protein 1 phosphorylation, which mediate mitochondrial fusion and fission, respectively. Mitochondria of fat-1 mice exhibited enhanced oxygen consumption rate, fatty acid β-oxidation, and energy substrate utilization as determined by high-resolution respirometry, [1- 14 C]-oleate oxidation and nicotinamide adenine dinucleotide hydride/dihydroflavine-adenine dinucleotide production, respectively. Untargeted lipidomics identified a rich hepatic omega-3-PUFA composition and a specific docosahexaenoic acid (DHA)-enriched lipid fingerprint in fat-1 mice. Targeted lipidomics uncovered a higher content of DHA-derived lipid autacoids, namely resolvin D1 and maresin 1, which rescued hepatocytes from TNFα-induced mitochondrial dysfunction, and unblocked the tricarboxylic acid cycle flux and metabolic utilization of long-chain acyl-carnitines, amino acids, and carbohydrates. Importantly, fat-1 mice were protected against mitochondrial injury induced by obesogenic and fibrogenic insults. Our data uncover the importance of a lipid membrane composition rich in DHA and its lipid autacoid derivatives to have optimal hepatic mitochondrial and metabolic efficiency.