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

TY - JOUR

T1 - Loss of hepatic SMLR1 causes hepatosteatosis and protects against atherosclerosis due to decreased hepatic VLDL secretion

AU - van Zwol, Willemien

AU - Rimbert, Antoine

AU - Wolters, Justina C

AU - Smit, Marieke

AU - Bloks, Vincent W

AU - Kloosterhuis, Niels J

AU - Huijkman, Nicolette C A

AU - Koster, Mirjam H

AU - Tharehalli, Umesh

AU - de Neck, Simon M

AU - Bournez, Colin

AU - Fuh, Marceline M

AU - Kuipers, Jeroen

AU - Rajan, Sujith

AU - de Bruin, Alain

AU - Ginsberg, Henry N

AU - van Westen, Gerard J P

AU - Hussain, M Mahmood

AU - Scheja, Ludger

AU - Heeren, Joerg

AU - Zimmerman, Philip

AU - van de Sluis, Bart

AU - Kuivenhoven, Jan Albert

N1 - © 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

PY - 2023/11/1

Y1 - 2023/11/1

N2 - BACKGROUND AND AIMS: The assembly and secretion of VLDL from the liver, a pathway that affects hepatic and plasma lipids, remains incompletely understood. We set out to identify players in the VLDL biogenesis pathway by identifying genes that are co-expressed with the MTTP gene that encodes for microsomal triglyceride transfer protein, key to the lipidation of apolipoprotein B, the core protein of VLDL. Using human and murine transcriptomic data sets, we identified small leucine-rich protein 1 (SMLR1), encoding for small leucine-rich protein 1, a protein of unknown function that is exclusively expressed in liver and small intestine.APPROACH AND RESULTS: To assess the role of SMLR1 in the liver, we used somatic CRISPR/CRISPR-associated protein 9 gene editing to silence murine Smlr1 in hepatocytes (Smlr1-LKO). When fed a chow diet, male and female mice show hepatic steatosis, reduced plasma apolipoprotein B and triglycerides, and reduced VLDL secretion without affecting microsomal triglyceride transfer protein activity. Immunofluorescence studies show that SMLR1 is in the endoplasmic reticulum and Cis-Golgi complex. The loss of hepatic SMLR1 in female mice protects against diet-induced hyperlipidemia and atherosclerosis but causes 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: We propose a role for SMLR1 in the trafficking of VLDL from the endoplasmic reticulum to the Cis-Golgi complex. While this study uncovers SMLR1 as a player in the VLDL assembly, trafficking, and secretion pathway, it also shows that NASH can occur with undisturbed glucose homeostasis and atheroprotection.

AB - BACKGROUND AND AIMS: The assembly and secretion of VLDL from the liver, a pathway that affects hepatic and plasma lipids, remains incompletely understood. We set out to identify players in the VLDL biogenesis pathway by identifying genes that are co-expressed with the MTTP gene that encodes for microsomal triglyceride transfer protein, key to the lipidation of apolipoprotein B, the core protein of VLDL. Using human and murine transcriptomic data sets, we identified small leucine-rich protein 1 (SMLR1), encoding for small leucine-rich protein 1, a protein of unknown function that is exclusively expressed in liver and small intestine.APPROACH AND RESULTS: To assess the role of SMLR1 in the liver, we used somatic CRISPR/CRISPR-associated protein 9 gene editing to silence murine Smlr1 in hepatocytes (Smlr1-LKO). When fed a chow diet, male and female mice show hepatic steatosis, reduced plasma apolipoprotein B and triglycerides, and reduced VLDL secretion without affecting microsomal triglyceride transfer protein activity. Immunofluorescence studies show that SMLR1 is in the endoplasmic reticulum and Cis-Golgi complex. The loss of hepatic SMLR1 in female mice protects against diet-induced hyperlipidemia and atherosclerosis but causes 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: We propose a role for SMLR1 in the trafficking of VLDL from the endoplasmic reticulum to the Cis-Golgi complex. While this study uncovers SMLR1 as a player in the VLDL assembly, trafficking, and secretion pathway, it also shows that NASH can occur with undisturbed glucose homeostasis and atheroprotection.

U2 - 10.1002/hep.32709

DO - 10.1002/hep.32709

M3 - SCORING: Journal article

C2 - 36053190

VL - 78

SP - 1418

EP - 1432

JO - HEPATOLOGY

JF - HEPATOLOGY

SN - 0270-9139

IS - 5

ER -