April 05, 2023 Omega-3 fatty acid-derived lipid mediators preserve mitocondrial function in metabolic-associated fatty liver disease The study conducted in mice provides new insights on the protective effects of omega-3 polyunsaturated fatty acids in metabolic-associated fatty liver disease.

BARCELONA—Metabolic-associated fatty liver disease (MAFLD) is a condition caused by accumulation of extra fat in the liver that can result in severe liver injury. A new study in mice highlights the role of lipid bioactive products of omega-3 polyunsaturated fatty acid (PUFA) in helping preserve hepatocyte mitochondria function and mitigating the pathophysiological effects associated with fatty liver disease. The study, published on 1 April 2023 in Hepatology, provides the mechanistic basis by which transgenic fat-1 mice, which carry an enzyme that endogenously replaces membrane omega-6-polyunsaturated PUFAs by omega-3 PUFAs, become resistant to liver disease and likely other inflammatory diseases characterized by mitochondrial dysfunction.

Researchers at EF CLIF, Hospital Clínic de Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (Spain); Barcelona Biomedical Research Institute (Spain); Massachusetts General Hospital and Harvard Medical School (MA, USA); and RIKEN Center for Integrative Medicine Sciences and Keio University (Japan), reported improved hepatocyte mitochondrial fusion/fission balance in fat-1 mice compared to wild type animals. Changes in shape are known to influence the mitochondrial energy output and production of reactive oxygen species, suggesting that the omega-3 PUFA-enriched tissue microenvironment may contribute to a superior mitochondrial metabolic capacity and function. Indeed, mitochondria in fat-1 mice showed higher oxygen consumption rate, increased fatty acid β-oxidation, and prioritization of intermediates of the tricarboxylic acid cycle (i.e., succinate and citrate) to produce high energy electron carriers to supply to the mitochondrial electron transport chain.

Liver tissue isolated from fat-1 mice presented a distinct composition of phospholipids containing decosahexaenoic acid (DHA) – an omega-3 PUFA precursor of bioactive lipid autacoids that promotes resolution of inflammation protecting the tissue againts injury. In fat-1 mice, researchers found increased levels of the lipid autacoids resolvin D1 and 7(R)-maresin 1 which had the ability to rescue mitochondrial function in wild type hepatocytes treated with the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα).

Interestingly, fat-1 mice on high-fat diet were resistant to induced hepatic steatosis and showed reduced liver injury compared with wild type mice under the same diet, with fat-1 mice retaining higher respiration capacity (i.e., oxygen consumption rate) and mitochondrial fatty acid β-oxidation than wild type animals. Moreover, fat-1 mice fed on a choline-deficient, L-amino acid-defined high-fat fibrogenic diet appeared to limit the extent of liver fibrosis providing further evidence for omega-3 PUFAs in preventing mitochondrial dysfunction induced by obesogenic or fibrogenic insults.

“Lipids, especially polyunsaturated fatty acids, not only play a role as cellular structural components and energy source but also as precursors of biologically active lipid derivatives. In the case of omega-6 polyunsaturated fatty acids the lipid derivatives (for example prostaglandins) are pro-inflammatory and immunosuppressive. In contrast, for omega-3 polyunsaturated fatty acids, the lipid derivatives are anti-inflammatory and promote the resolution of inflammation. This is the main reason why replacing omega-6s by omega-3s provides health benefits”, said co-corresponding author Joan Clària, Principal Investigator at EF CLIF and Hospital Clínic-IDIBAPS, Spain.

“Today it is well known that the omega-3s exert beneficial effects on inflammation and immune system, but we are still wondering which are the undelying cellular and molecular mechanisms. Thanks to this study, we come closer to understanding how these lipids have a more profound effect at the cellular energy level”, said first author Cristina López-Vicario, potsdoctoral reseasercher at Hospital Clínic-IDIBAPS, Spain.

“The results of our investigation lead us to think that not only we could prevent having an unhealthy liver with a balanced diet rich in highly anti-inflammatory omega-3 fatty acids, but fibrotic and injured liver can be reverted by increasing the intake of these essential fatty acids”, added López-Vicario.

“We are currently working on a project exploring the benefits of omega-3s in more advanced stages of liver disease. Particularly, we are working with fat-1 mice induced to cirrhosis in which we precipitate acute-on-chronic liver failure by a model of polymicrobial peritonitis. Our ultimate goal is to explore the importace of maintaining an adequate lipid nutritional support with essential fatty acids, especially of the omega-3 family, in critically ill patients”, concluded Clària.

This study was sponsored by the European Foundation for the Study of Chronic Failure (EF CLIF).

Other authors on the study are David Sebastián, Mireia Casulleras, Marta Duran-Güell, Roger Flores-Costa, Ferran Aguilar, Juan José Lozano, Ingrid W. Zhang, Esther Titos, Jing X. Kang, Antonio Zorzano, and Makoto Arita.

Publication information

López-Vicario, C.; Sebastián, D.; Casulleras, M.; Duran-Güell, M.; Flores-Costa, R.; Aguilar, F.; Lozano, J. J.; Zhang, I. W.; Titos, E.; Kang, J. X.; Zorzano, A.; Arita, M.; Clària, J. Essential lipid autacoids rewire mitochondrial energy efficiency in metabolic dysfunction-associated fatty liver disease. Hepatology 2023, 77 (4): 1303–1318. DOI: 10.1002/hep.32647