Willemien Van Zwol (Netherlands)
UMCG Pediatrics, section; Molecular GeneticsAuthor Of 1 Presentation
O030 - A novel gene affecting VLDL assembly/secretion (ID 946)
Abstract
Background and Aims
Compromised secretion of very low-density lipoprotein (VLDL) can result in hepatic lipid accumulation, a risk factor for non-alcoholic fatty liver disease (NAFLD). Basic knowledge of VLDL assembly and the secretion pathway may help to find solutions for NAFLD. Here, we present a novel gene, SMLR1, identified through contextual co-expression analysis with APOC3 as anchor. SMLR1 expression is strictly confined to liver and small intestine. Here, we present a first study on the role of SMLR1 in hepatic and plasma lipid metabolism.
Methods
Using somatic CRISPR/Cas9 gene editing, we downregulated Smlr1 expression in livers of wild-type male and female mice, fed a chow diet. Liver lipids were extracted, and VLDL secretion rate was assessed after poloxamer injection. Lipoprotein profiling was conducted by FPLC. Immortalized human hepatoma cells where used for localization studies.
Results
Downregulation of Smlr1 at the mRNA level (80%) and protein level (67%), resulted in 50% reduction of plasma cholesterol and triglycerides (p<0.001 for both), and increased hepatic lipid levels (>2.9fold, p<0.001). In line, VLDL secretion rate was reduced by 45% (Fig1A). Both LDL and HDL cholesterol were reduced (Fig1B). SMLR1 was found to be localized in the endoplasmic reticulum (ER) and Golgi complex.
Conclusions
Smlr1 is a key gene in the regulation of plasma and hepatic lipid metabolism. It is noteworthy that, until now, the phenotype resembles a phenocopy of the liver-specific MTTP-/- mice. SMLR1 is localized in the ER and Golgi complex and anticipated to play a role in the trafficking of lipoproteins.
Presenter of 1 Presentation
O030 - A novel gene affecting VLDL assembly/secretion (ID 946)
Abstract
Background and Aims
Compromised secretion of very low-density lipoprotein (VLDL) can result in hepatic lipid accumulation, a risk factor for non-alcoholic fatty liver disease (NAFLD). Basic knowledge of VLDL assembly and the secretion pathway may help to find solutions for NAFLD. Here, we present a novel gene, SMLR1, identified through contextual co-expression analysis with APOC3 as anchor. SMLR1 expression is strictly confined to liver and small intestine. Here, we present a first study on the role of SMLR1 in hepatic and plasma lipid metabolism.
Methods
Using somatic CRISPR/Cas9 gene editing, we downregulated Smlr1 expression in livers of wild-type male and female mice, fed a chow diet. Liver lipids were extracted, and VLDL secretion rate was assessed after poloxamer injection. Lipoprotein profiling was conducted by FPLC. Immortalized human hepatoma cells where used for localization studies.
Results
Downregulation of Smlr1 at the mRNA level (80%) and protein level (67%), resulted in 50% reduction of plasma cholesterol and triglycerides (p<0.001 for both), and increased hepatic lipid levels (>2.9fold, p<0.001). In line, VLDL secretion rate was reduced by 45% (Fig1A). Both LDL and HDL cholesterol were reduced (Fig1B). SMLR1 was found to be localized in the endoplasmic reticulum (ER) and Golgi complex.
Conclusions
Smlr1 is a key gene in the regulation of plasma and hepatic lipid metabolism. It is noteworthy that, until now, the phenotype resembles a phenocopy of the liver-specific MTTP-/- mice. SMLR1 is localized in the ER and Golgi complex and anticipated to play a role in the trafficking of lipoproteins.