Altered sphingolipid biosynthetic flux and lipoprotein trafficking contribute to trans-fat-induced atherosclerosis

Jivani M Gengatharan; Michal K Handzlik; Zoya Y Chih; Maureen L Ruchhoeft; Patrick Secrest; Ethan L Ashley; Courtney R Green; Martina Wallace; Philip L S M Gordts; Christian M Metallo

doi:10.1016/j.cmet.2024.10.016

Altered sphingolipid biosynthetic flux and lipoprotein trafficking contribute to trans-fat-induced atherosclerosis

Cell Metab. 2024 Nov 13:S1550-4131(24)00412-1. doi: 10.1016/j.cmet.2024.10.016. Online ahead of print.

Affiliations

¹ Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
² Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
³ Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
⁴ School of Agriculture and Food Science, University College Dublin, Dublin, Ireland.
⁵ Department of Medicine, University of California, San Diego, La Jolla, CA, USA; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA.
⁶ Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA. Electronic address: metallo@salk.edu.

PMID: 39547233
DOI: 10.1016/j.cmet.2024.10.016

Abstract

Dietary fat drives the pathogenesis of atherosclerotic cardiovascular disease (ASCVD), particularly through circulating cholesterol and triglyceride-rich lipoprotein remnants. Industrially produced trans-unsaturated fatty acids (TFAs) incorporated into food supplies significantly promote ASCVD. However, the molecular trafficking of TFAs responsible for this association is not well understood. Here, we demonstrate that TFAs are preferentially incorporated into sphingolipids by serine palmitoyltransferase (SPT) and secreted from cells in vitro. Administering high-fat diets (HFDs) enriched in TFAs to Ldlr^-/- mice accelerated hepatic very-low-density lipoprotein (VLDL) and sphingolipid secretion into circulation to promote atherogenesis compared with a cis-unsaturated fatty acid (CFA)-enriched HFD. SPT inhibition mitigated these phenotypes and reduced circulating atherogenic VLDL enriched in TFA-derived polyunsaturated sphingomyelin. Transcriptional analysis of human liver revealed distinct regulation of SPTLC2 versus SPTLC3 subunit expression, consistent with human genetic correlations in ASCVD, further establishing sphingolipid metabolism as a critical node mediating the progression of ASCVD in response to specific dietary fats.

Keywords: SPTLC3; TRL remnant; VLDL; atherosclerosis; lipoprotein; monounsaturated fatty acid; myriocin; sphingolipid; sphingomyelin; trans fatty acid.