Impaired unsaturated fatty acid elongation alters mitochondrial function and accelerates metabolic dysfunction-associated steatohepatitis progression

Abstract

Background and aims: Although qualitative and quantitative alterations in liver Polyunsaturated Fatty Acids (PUFAs) are observed in MASH in humans, a causal relationship of PUFAs biosynthetic pathways is yet to be clarified. ELOVL5, an essential enzyme in PUFA elongation regulates hepatic triglyceride metabolism. Nonetheless, the long-term consequences of elongase disruption, particularly in murine models of MASH, have not been evaluated.

Approach & results: In humans, transcriptomic data indicated that PUFAs biosynthesis enzymes and notably ELOVL5 were induced during MASH progression. Moreover, gene module association determination revealed that ELOVL5 expression was associated with mitochondrial function in both humans and mice. WT and Elovl5-deficient mice were fed a high-fat, high-sucrose (HF/HS) diet for four months. Elovl5 deficiency led to limited systemic metabolic alterations but significant hepatic phenotype was observed in Elovl5-/- mice after the HF/HS diet, including hepatomegaly, pronounced macrovesicular and microvesicular steatosis, hepatocyte ballooning, immune cell infiltration, and fibrosis. Lipid analysis confirmed hepatic triglyceride accumulation and a reshaping of FA profile. Transcriptomic analysis indicated significant upregulation of genes involved in immune cell recruitment and fibrosis, and downregulation of genes involved in oxidative phosphorylation in Elovl5-/- mice. Alterations of FA oxidation and energy metabolism were confirmed by non-targeted metabolomic approach. Analysis of mitochondrial function in Elovl5-/- mice showed morphological alterations, qualitative cardiolipin changes with an enrichment in species containing shorter unsaturated FAs, and decreased activity of I and III respiratory chain complexes.

Conclusion: Enhanced susceptibility to diet-induced MASH and fibrosis in Elovl5-/- mice is intricately associated with disruptions in mitochondrial homeostasis, stemming from a profound reshaping of mitochondrial lipids, notably cardiolipins.

Keywords: Cardiolipins; ELOVL5; MASH; MASLD; PUFAs; Steatosis.