Uchiyama Lauren F, Nguyen Alexander, Qian Kevin, Cui Liujuan, Pham Khoi T, Xiao Xu, Gao Yajing, Shimanaka Yuta, Tol Marcus J, Vergnes Laurent, Reue Karen, Tontonoz Peter
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
Department of Biological Chemistry, University of California, Los Angeles, CA 90095.
Proc Natl Acad Sci U S A. 2025 Apr 29;122(17):e2426338122. doi: 10.1073/pnas.2426338122. Epub 2025 Apr 21.
Ketogenesis requires fatty acid flux from intracellular (lipid droplets) and extrahepatic (adipose tissue) lipid stores to hepatocyte mitochondria. However, whether interorganelle contact sites regulate this process is unknown. Recent studies have revealed a role for Calsyntenin-3β (CLSTN3β), an endoplasmic reticulum-lipid droplet contact site protein, in the control of lipid utilization in adipose tissue. Here, we show that expression is induced in the liver by the nuclear receptor PPARα in settings of high lipid utilization, including fasting and ketogenic diet feeding. Hepatocyte-specific loss of CLSTN3β in mice impairs ketogenesis independent of changes in PPARα activation. Conversely, hepatic overexpression of CLSTN3β promotes ketogenesis in mice. Mechanistically, CLSTN3β affects LD-mitochondria crosstalk, as evidenced by changes in fatty acid oxidation, lipid-dependent mitochondrial respiration, and the mitochondrial integrated stress response. These findings define a function for CLSTN3β-dependent membrane contacts in hepatic lipid utilization and ketogenesis.
生酮作用需要脂肪酸从细胞内（脂滴）和肝外（脂肪组织）脂质储存部位转运至肝细胞线粒体。然而，细胞器间接触位点是否调控这一过程尚不清楚。最近的研究揭示了一种内质网 - 脂滴接触位点蛋白钙黏连蛋白 -3β（CLSTN3β）在脂肪组织脂质利用控制中的作用。在此，我们表明，在包括禁食和生酮饮食喂养等高脂质利用情况下，核受体PPARα可诱导肝脏中CLSTN3β的表达。小鼠肝细胞特异性缺失CLSTN3β会损害生酮作用，且与PPARα激活的变化无关。相反，肝脏中CLSTN3β的过表达会促进小鼠的生酮作用。从机制上讲，CLSTN3β影响脂滴 - 线粒体的相互作用，脂肪酸氧化、脂质依赖性线粒体呼吸以及线粒体综合应激反应的变化证明了这一点。这些发现确定了CLSTN3β依赖性膜接触在肝脏脂质利用和生酮作用中的功能。
