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

• DOI: 10.1016/j.cmet.2023.10.008
• Publication Date: 2023-10-30T15:05:15Z
• Authors: Panu K. Luukkonen; Kimmo Porthan; Noora Ahlholm; Fredrik Rosqvist; Sylvie Dufour; Xian-Man Zhang; Tiina E. Lehtimäki; Wenla Seppänen; Marju Orho-Melander; Leanne Hodson; Kitt Falk Petersen; Gerald I. Shulman; Hannele Yki-Järvinen
• Keywords: Medicin och hälsovetenskap; patatin-like phospholipase domain containing protein 3; 3-Hydroxybutyric Acid; Lipogenesis; NASH; reductive stress; Gastroenterology and Hepatology; Medical and Health Sciences; 3. Good health; GDF-15; Mitochondria; Biomedicine; Liver; ketogenic diet; Non-alcoholic Fatty Liver Disease; NAD+; NAFLD; redox; mitochondrial dysfunction; NADH; Humans; Genetic Predisposition to Disease; Gastroenterologi och hepatologi

The 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.