PPARα regulates ER–lipid droplet protein Calsyntenin-3β to promote ketogenesis in hepatocytes
Abstract
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 Clstn3b 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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (12)
Lauren F. Uchiyama
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California
Alexander Nguyen
Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California
Kevin Qian
Department of Chemistry
Liujuan Cui
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California
Khoi T. Pham
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California
Xu Xiao
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California
Yajing Gao
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California
Yuta Shimanaka
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California
Marcus J. Tol
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California
Laurent Vergnes
Department of Human Genetics, University of California
Karen Reue
Department of Human Genetics, University of California
Peter Tontonoz
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California