Cellular and Molecular Mechanisms of lean MAFLD

Abstract

Metabolic dysfunction–associated fatty liver disease (MAFLD) includes a subgroup with normal body mass index, termed lean MAFLD, who show increased mortality despite a relatively favourable metabolic profile. The mechanisms underlying this paradox remain unclear. This thesis investigates pathways contributing to adverse outcomes in lean MAFLD, focusing on telomere dynamics, epigenetic regulation of growth differentiation factor-15 (GDF-15), and mitochondrial alterations. Clinical and population-based analyses demonstrate that lean MAFLD is associated with shorter telomere length compared to non-lean MAFLD. Telomere shortening correlates with hepatic inflammation, fibrosis, and oxidative stress, and independently predicts all-cause mortality. Experimental data show that oxidative stress induces telomere attrition and reduces telomerase activity. DNA methylation–derived GDF-15 (DNAm-GDF15) is elevated in lean MAFLD and associated with mortality independent of traditional risk factors. DNAm-GDF15 negatively correlates with telomere length and partially mediates its association with mortality. Mitochondrial analysis reveals enlarged mitochondria, reduced mitochondrial DNA, decreased respiratory chain expression, and impaired quality control, alongside increased oxidative stress. Together, these findings indicate that impaired metabolic adaptation in lean MAFLD drives oxidative stress, telomere attrition, epigenetic dysregulation, and mitochondrial dysfunction, contributing to disease progression and mortality.