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
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 - This article is protected by copyright. All rights reserved.
PY - 2023/11
Y1 - 2023/11
N2 - 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.
AB - 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.
U2 - 10.1002/hep.32709
DO - 10.1002/hep.32709
M3 - Article
C2 - 36053190
SN - 0270-9139
VL - 78
SP - 1418
EP - 1432
JO - Hepatology
JF - Hepatology
IS - 5
ER -