Loss of hepatic SMLR1 causes hepatosteatosis and protects against atherosclerosis due to decreased hepatic VLDL secretion

Willemien van Zwol, Antoine Rimbert, Justina C Wolters, Marieke Smit, Vincent W Bloks, Niels J Kloosterhuis, Nicolette Huijkman, Mirjam H Koster, Umesh Tharehalli, Simon M de Neck, Colin Bournez, Marceline M Fuh, Jeroen Kuipers, Sujith Rajan, Alain de Bruin, Henry N Ginsberg, Gerard J P van Westen, M Mahmood Hussain, Ludger Scheja, Joerg HeerenPhilip Zimmerman, Bart van de Sluis, Jan Albert Kuivenhoven*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND AND AIMS: The assembly and secretion of very low-density lipoproteins (VLDL) from the liver, a pathway that affects hepatic and plasma lipids, remains incompletely understood. We set out to identify new players in the VLDL biogenesis pathway through identifying genes that are co-expressed with the MTTP gene which encodes for microsomal triglyceride transfer protein (MTP), key to the lipidation of apolipoprotein (apo) B, the core protein of VLDL. Using human and murine transcriptomic datasets, we identified SMLR1, encoding for small leucine-rich protein 1, a protein of unknown function, which is exclusively expressed in liver and small intestine.

APPROACH AND RESULTS: To assess the role of SMLR1 in the liver, we used somatic CRISPR/Cas9 gene editing to silence murine Smlr1 in hepatocytes (Smlr1-LKO). When fed a chow diet, male and female mice show hepatic steatosis, reduced plasma apoB and triglycerides, and reduced VLDL secretion without affecting MTP activity. Immunofluorescence studies show that SMLR1 is in the endoplasmic reticulum (ER) and Cis-Golgi complex. The loss of hepatic SMLR1 in female mice protects against diet-induced hyperlipidemia and atherosclerosis but causes non-alcoholic steatohepatitis (NASH). On a high-fat high cholesterol diet insulin and glucose tolerance tests did not reveal differences in male Smlr1-LKO mice versus controls.

CONCLUSIONS: In conclusion, we propose a role for SMLR1 in the trafficking of VLDL from the ER to the Cis-Golgi complex. While this study uncovers SMLR1 as a new player in the VLDL assembly, trafficking, and secretion pathway, it also shows that NASH can occur with undisturbed glucose homeostasis and atheroprotection.

Original languageEnglish
JournalHepatology
DOIs
Publication statusE-pub ahead of print - 2-Sep-2022

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