{Reference Type}: Journal Article
{Title}: Telomere length and mortality in lean MAFLD: the other face of metabolic adaptation.
{Author}: Alarabi M;Pan Z;Romero-Gómez M;George J;Eslam M;
{Journal}: Hepatol Int
{Volume}: 0
{Issue}: 0
{Year}: 2024 Jun 20
{Factor}: 9.029
{DOI}: 10.1007/s12072-024-10701-6
{Abstract}: <B>OBJECTIVE: </B>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.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.