Frontiers in Nutrition · 10 authors, 6 centres
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This study investigated the interaction between the PNPLA3 I148M genetic variant and niacin (vitamin B3) in patients with non-alcoholic fatty liver disease (NAFLD). The central result was that the I148M variant was independently associated with lower serum niacin levels and that functional PNPLA3 protein was required for niacin to effectively reduce liver fat in cell models.
The study enrolled three human NAFLD cohorts: a Discovery cohort (n=172) for dietary and serum niacin assessment, a Validation cohort (n=358) to confirm serum niacin findings, and a Transcriptomic cohort (n=183) for hepatic NAD metabolism gene analysis. In vitro experiments used Hep3B (wild-type) and HepG2 (I148M) hepatoma cells. Central results showed that NAFLD patients carrying the I148M variant had lower serum niacin levels, which was independently associated with the genotype. Hepatic transcriptomic data revealed reduced expression of the canonical NAD synthesis gene NAPRT1 in I148M carriers. In vitro, PNPLA3 loss-of-function impaired niacin-induced NAD production and reduced niacin's efficacy in clearing hepatocellular triglycerides. Niacin's fat-reducing effects were mediated through the ERK1/2/AMPK/SIRT1 pathway, leading to reduced de novo lipogenesis, but this mechanism was blunted in cells with the PNPLA3 variant. The findings suggest a gene-nutrient crosstalk that could inform personalized nutritional interventions in genetically predisposed NAFLD patients.
