The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans

Cell Metab. 2023 Oct 20:S1550-4131(23)00377-7. doi: 10.1016/j.cmet.2023.10.008. Online ahead of print.ABSTRACTThe PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the effect of this variant on hepatic metabolism in homozygous carriers and non-carriers under multiple physiological conditions with state-of-the-art stable isotope techniques. After an overnight fast, carriers had higher plasma β-hydroxybutyrate concentrations and lower hepatic de novo lipogenesis (DNL) compared to non-carriers. After a mixed meal, fatty acids were channeled toward ketogenesis in carriers, which was associated with an increase in hepatic mitochondrial redox state. During a ketogenic diet, carriers manifested increased rates of intrahepatic lipolysis, increased plasma β-hydroxybutyrate concentrations, and decreased rates of hepatic mitochondrial citrate synthase flux. These studies demonstrate that homozygous PNPLA3 I148M carriers have hepatic mitochondrial dysfunction leading to reduced DNL and channeling of carbons to ketogenesis. These findings have implications for understanding why the PNPLA3 variant predisposes to progressive liver disease.PMID:37909034 | DOI:10.1016/j.cmet.2023.10.008

Source: Cell Metabolism - November 1, 2023 Category: Cytology Authors: Panu K Luukkonen Kimmo Porthan Noora Ahlholm Fredrik Rosqvist Sylvie Dufour Xian-Man Zhang Tiina E Lehtim äki Wenla Sepp änen Marju Orho-Melander Leanne Hodson Kitt Falk Petersen Gerald I Shulman Hannele Yki-J ärvinen Source Type: research