酮发生
脂肪生成
内科学
内分泌学
脂解
脂肪肝
酮体
生物
线粒体
酮症
化学
新陈代谢
医学
生物化学
疾病
糖尿病
脂肪组织
作者
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
出处
期刊:Cell Metabolism
[Elsevier]
日期:2023-11-01
卷期号:35 (11): 1887-1896.e5
被引量:13
标识
DOI:10.1016/j.cmet.2023.10.008
摘要
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.
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