PPARα regulates ER-lipid droplet protein Calsyntenin-3β to promote ketogenesis in hepatocytes

• 成果类型: Article
• 署名作者: 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
• 署名单位: University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10805
• DOI: 10.1073/pnas.2426338122
• 发表日期: 2025-04-28
• 关键词: activated receptor-alpha; fatty-acid oxidation; integrated stress-response; liver-disease; mitochondria; GROWTH; mouse; fsp27

摘要

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 protein, in the control of lipid utilization in adipose tissue. Here, we show that Clstn3b expression is induced in the liver by the nuclear receptor PPAR alpha in settings of high lipid utilization, including fasting and ketogenic diet feeding. Hepatocyte- specific loss of CLSTN3 beta in mice impairs ketogenesis independent of changes in PPAR alpha activation. Conversely, hepatic overexpression of CLSTN3 beta promotes ketogenesis in mice. Mechanistically, CLSTN3 beta 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 CLSTN3 beta- dependent membrane contacts in hepatic lipid utilization and ketogenesis.