UCLA

Ketogenesis requires fatty acid influx from stored lipid droplets or extrahepatic tissues to hepatic mitochondria. However, whether inter-organelle contact sites can regulate this process is unknown. Recent studies have revealed a role for Calsyntenin-3b (Clstn3b), an endoplasmic reticulum-lipid droplet contact site protein, in control of lipid utilization in adipose tissue. Here we show that Clstn3b transcription is induced in liver by PPARa in settings of high lipid utilization, including fasting and ketogenic diet feeding. Hepatocyte-specific loss of Clstn3b in mice inhibits ketogenesis independent of changes in PPARa activation. Conversely, hepatic overexpression of Clstn3b promotes ketogenesis in mice. Furthermore, the absence of Clstn3b alters LD- mitochondrial crosstalk, as revealed by impaired fatty acid oxidation and mitochondrial respiration, and a decreased mitochondrial integrated stress response. These findings define an important function for Clstn3b in ketogenesis and lipid utilization in hepatocytes.