小柯机器人

美国耶鲁医学院Panu K. Luukkonen团队探明了PNPLA3 I148M变异增加人类生酮，降低肝脏新生脂肪生成(DNL)和线粒体功能。相关论文于2023年10月30日发表在《细胞—代谢》杂志上。

他们利用最先进的稳定同位素技术研究了该变异在多种生理条件下，对纯合子携带者和非携带者肝脏代谢的影响。禁食一夜后，与非携带者相比，携带者血浆β-羟基丁酸盐浓度更高，肝脏DNL更低。在混合膳食后，脂肪酸被引导到携带者的生酮过程中，这与肝脏线粒体氧化还原状态的增加有关。在生酮饮食期间，携带者表现出肝内脂肪分解率增加，血浆β-羟基丁酸盐浓度增加，肝脏线粒体柠檬酸合成酶通量降低。

这些研究表明，纯合子PNPLA3 I148M携带者存在肝脏线粒体功能障碍，导致DNL减少和碳通道生成酮。这些发现有助于理解为什么PNPLA3变异容易导致进行性肝病。

据了解，PNPLA3 I148M变异是所有阶段脂肪肝疾病的主要遗传危险因素，但其潜在的病理生理机制尚不清楚。

附：英文原文

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

Author: Panu K. Luukkonen, Kimmo Porthan, Noora Ahlholm, Fredrik Rosqvist, Sylvie Dufour, Xian-Man Zhang, Tiina E. Lehtimki, Wenla Seppnen, Marju Orho-Melander, Leanne Hodson, Kitt Falk Petersen, Gerald I. Shulman, Hannele Yki-Jrvinen

Issue&Volume: 2023-10-30

Abstract: 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.

DOI: 10.1016/j.cmet.2023.10.008

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00377-7

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