At the origin: unravelling apoB-containing lipoprotein biogenesis
At the origin: unravelling apoB-containing lipoprotein biogenesis
Obesity affects an estimated 1 in 8 people worldwide and is associated with a range of metabolic complications. This includes dyslipidaemia, a major risk factor for atherosclerotic cardiovascular disease - the leading cause of death globally. Dyslipidaemia is characterised by elevated triglycerides and apolipoprotein B (apoB)–containing lipoproteins, yet the intracellular mechanisms governing their biogenesis and secretion remain incompletely understood. This thesis of Ankia Visser investigates novel regulators of lipoprotein metabolism, with a particular focus on the small intestine, and tools to better study the intracellular pathways involved in apoB-containing lipoprotein production.
Chylomicrons, the apoB-containing lipoproteins produced by the small intestine, are essential for delivering dietary lipids and lipid-soluble vitamins to peripheral tissues. This work reviews emerging evidence that chylomicron biogenesis involves previously unrecognised cellular components and highlights key gaps in understanding their intracellular trafficking and secretion. Using mouse models, this thesis demonstrates that small leucine-rich protein 1 (SMLR1), previously shown to regulate hepatic VLDL secretion, also plays a role in intestinal lipid handling.
In contrast, functional studies of glutamate-rich protein 4 (ERICH4), identified through transcriptomic analyses, revealed no detectable role in intestinal lipid metabolism in mice. Finally, this thesis describes the development of a transgenic mouse model designed to study intracellular apoB trafficking, highlighting current technical limitations in detecting apoB within cells.
Overall, this work advances understanding of the intracellular biology of apoB-containing lipoproteins and provides new insights into mechanisms underlying dyslipidaemia and metabolic disease.