Telomere length and mortality in lean MAFLD: the other face of metabolic adaptation

Healthy weight (lean) patients with metabolic dysfunction-associated fatty liver disease (MAFLD) have a more favorable metabolic and histological profile in cross-sectional studies compared with their non-lean counterparts. Paradoxically, they also have higher overall mortality. The underpinning pathophysiology of this paradox is not understood. Telomere attrition is associated with increased mortality in various diseases.

We investigated the role of telomere length in the pathogenesis of lean MAFLD in cohorts with biopsy-proven MAFLD (n = 303). We measured serum malondialdehyde (MDA) levels and hepatic 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (4-HNE) expression (reactive oxygen species (ROS) markers), growth/differentiation factor-15 (GDF-15) and tested the effect of H₂O₂ on telomere length and activity in hepatocyte cell lines. The association between leukocyte telomere length and mortality was examined.

Telomere length was significantly lower in patients with lean MAFLD (p < 0.001). They also demonstrated an increase in ROS levels and decreases in GDF-15. H₂O₂ induced telomere shortening and reducing telomere activity in hepatocyte cell lines. We subsequently confirmed that telomere length shortening at baseline is associated with increased hazards of all-cause mortality; the deleterious effect was more profound in lean people.

Differences in telomere length in part explain the increased mortality of lean compared to non-lean patients with MAFLD. The effect is in part mediated through ROS activation and provide opportunities for therapy.