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

Background and Aim: 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. Approach and Results: 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. Conclusion: 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.