Probing the regulation of cellular lipid metabolism by trans fatty acids and the lipid-sensitive ANGPTL4 protein

Abstract

A coordinated regulation of lipid metabolism is important in maintaining cardiometabolic health, since a dysregulation in lipid metabolism is implicated in hyperlipidaemia, insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis and coronary artery disease. This thesis has investigated the pre-clinical effects of dietary trans fatty acids, lipid-sensitive angiopoietin-like 4 (ANGPTL4) and muscle inflammation on cardiometabolic health. The aim is to further understand the metabolic and molecular mechanisms by which trans fatty acids, ANGPTL4 and muscle-specific inflammation impact cardiometabolic health in order to devise therapeutic strategies. Trans fatty acids are unsaturated fatty acids that contain at least one double bond in the trans configuration. In humans, the consumption of certain trans fatty acids is implicated in the onset and progression of cardiovascular diseases due in part to the ability of such trans fatty acids to raise the plasma levels of total and LDL-cholesterol, and decrease the levels of HDL-cholesterol. However, the underlying mechanisms for the deleterious effects of trans fatty acids are not fully understood. We show in C57Bl/6 mice that a diet enriched in industrial trans fatty acids from partially hydrogenated soybean oil promotes non-alcoholic fatty liver disease (NAFLD) compared to cis-unsaturated and saturated fatty acid diets. At the cellular level, we demonstrate in murine hepatocyte and adipocyte cell lines that the industrial fatty acid elaidate induces cholesterogenesis through enhanced expression and activity of sterol regulatory element binding protein 2 (SREBP2). ANGPTL4 is an inhibitor of lipoprotein lipase (LPL). LPL hydrolyses circulating triglycerides to generate fatty acids for uptake into tissues. Therefore, as an inhibitor of LPL, ANGPTL4 indirectly raises the levels of circulating triglycerides leading to an associated increased risk for cardiovascular diseases. However, the potential of inhibiting ANGPTL4 to lower the risk of cardiovascular diseases is hampered by lethal side-effects in ANGPTL4-deficient mice fed diets rich in saturated fatty acids. In this thesis, we demonstrate that ANGPTL4-deficient mice respond favourably to a trans fat diet than a saturated fat diet. Furthermore, we show that saturated fatty acids but not trans fatty acids induce inflammation and endoplasmic reticulum (ER) stress in murine macrophages. This thesis also characterised a novel ANGPTL4-hypomorphic mice model with only a partial expression of the N-terminal domain of ANGPTL4. Following a chronic high saturated fat diet challenge, the hypomorphs showed reduced levels of plasma triglycerides as the complete ANGPTL4-deficient mice. Interestingly, the hypomorphs showed attenuated and milder forms of the side-effects that occur in the complete ANGPTL4-deficient mice. Finally, this thesis has also examined the role of muscle specific inflammation on systemic glucose homeostasis. We found that skeletal muscle-specific inflammation via over-expression of monocyte chemoattractant protein-1 (MCP-1) does not affect systemic glucose and insulin sensitivity in mice. Taken together, this thesis has provided insight into the molecular mechanisms of trans fatty acids and highlighted the prospect of harnessing the therapeutic potential of ANGPTL4 inactivation for correcting cardiometabolic abnormalities.