From lowering plasma lipids to fight atherosclerosis to studies into the biogenesis of apoB-containing lipoproteins and their relationship with hepatic steatosis

To improve our understanding of lipid homeostasis, this thesis has focused on increasing our understanding of the production and secretion of apolipoprotein (apo)B containing lipoproteins in the liver (very low-density lipoprotein; VLDL) and the small intestine (chylomicrons).
This has led to the discovery and validation of small leucine-rich protein 1 (SMLR1) as a novel player in lipid metabolism: hepatic ablation of SMLR1 in mice results in major reductions in both plasma cholesterol and triglyceride levels and protects against atherosclerosis but also induces non-alcoholic fatty liver disease. Notably, this phenotype was not associated with insulin resistance. Further molecular studies show that proteins with roles in lipid droplet biology are physically associated with SMLR1 while ultrastructural studies reveal a close association between lipid droplets and VLDL biology that warrants further investigation.
We also identified a second candidate gene (ERICH4) encoding for glutamate-rich protein 4 which was predicted to play a role in the production of chylomicrons. Supported by prediction software and human genetic studies, we generated a whole-body ERICH4 knockout mouse model which unfortunately does not show a lipid phenotype. The current data do support however further studies into the role of ERICH4 in humans.
In addition, we critically examined the existing literature on the molecular aspects of VLDL assembly, trafficking and secretion machinery and highlighted current knowledge gaps. In conclusion, the work described in this thesis contributes to fundamental VLDL research potentially aiding the development of drugs targeting liver steatosis and atherosclerosis in cardiometabolic patients.