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U.S.A."],"published-print":{"date-parts":[[2025,4,29]]},"abstract":"<jats:p>\n                    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-3\u03b2 (CLSTN3\u03b2), an endoplasmic reticulum\u2013lipid droplet contact site protein, in the control of lipid utilization in adipose tissue. Here, we show that\n                    <jats:italic>Clstn3b<\/jats:italic>\n                    expression is induced in the liver by the nuclear receptor PPAR\u03b1 in settings of high lipid utilization, including fasting and ketogenic diet feeding. Hepatocyte-specific loss of CLSTN3\u03b2 in mice impairs ketogenesis independent of changes in PPAR\u03b1 activation. Conversely, hepatic overexpression of CLSTN3\u03b2 promotes ketogenesis in mice. Mechanistically, CLSTN3\u03b2 affects LD\u2013mitochondria 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\u03b2-dependent membrane contacts in hepatic lipid utilization and ketogenesis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2426338122","type":"journal-article","created":{"date-parts":[[2025,4,21]],"date-time":"2025-04-21T15:07:51Z","timestamp":1745248071000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":7,"title":["PPAR\u03b1 regulates ER\u2013lipid droplet protein Calsyntenin-3\u03b2 to promote ketogenesis in hepatocytes"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6574-0064","authenticated-orcid":false,"given":"Lauren F.","family":"Uchiyama","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California","place":["Los Angeles"]},{"name":"Department of Biological Chemistry, University of California","place":["Los Angeles"]},{"name":"Molecular Biology Institute, University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California","place":["Los Angeles"]},{"name":"Department of Biological Chemistry, University of California","place":["Los Angeles"]},{"name":"Molecular Biology Institute, University of California","place":["Los 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Liang A. Damdimopoulos E. Treuter R. Fan Data from \u201cHepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPAR\u03b1.\u201d Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE113157. Deposited 12 March 2019.","DOI":"10.1038\/s41467-019-09524-z"},{"key":"e_1_3_4_60_2","unstructured":"D. Li Data from \u201cThe NIEHS TaRGET II Consortium and environmental epigenomics.\u201d Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE146508. Deposited 20 May 2020."},{"key":"e_1_3_4_61_2","doi-asserted-by":"crossref","unstructured":"M. Boergesen Data from \u201cGenome-Wide Profiling of Liver X Receptor Retinoid X Receptor and Peroxisome Proliferator-Activated Receptor \u03b1 in Mouse Liver Reveals Extensive Sharing of Binding Sites.\u201d Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE35262. 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