Studies on the regulation of hepatic and intestinal lipid metabolism

Disturbances in the lipid homeostasis can result in a wide variety of different diseases and symptoms. This thesis is focused on the regulation of cholesterol metabolism and its relation to atherosclerosis development, and the effect of mitochondrial (mt)DNA depletion on hepatic β-oxidation of fatty acids. ApoE deficient mice spontaneously develop atherosclerosis due to accumulation of chylomicron remnants in the circulation, a process highly dependent on intestinal cholesterol absorption. The lack of functional ApoE prevents receptor mediated uptake of lipoproteins, leading to very high levels of circulating cholesterol. We used two approaches to test the influence of plasma cholesterol levels on atherosclerosis development in ApoE deficient mice. In paper I we disrupted the Cyp8b1 gene to disable the endogenous synthesis of cholic acid and thereby reduce the intestinal absorption of cholesterol. Cyp8b1/ApoE double knockout mice displayed reduced atherosclerotic lesions in aorta, reduced cholesterol levels in plasma and liver and reduced intestinal cholesterol absorption compared to ApoE knockout mice. In paper II we treated ApoE deficient mice with the thyroid receptor βmodulator GC-1. Supplementation with thyroid hormone reduces plasma cholesterol in humans and rodents; this effect is mediatedby the thyroid receptor isoform β(TRβ). We found that oral administration of GC-1 reduced atherosclerosis after 20 weeks of treatment. This reduction was accompanied by increased hepatic LDL-receptorexpression, bile acid synthesis and fecal bile acid excretion, butserum cholesterol levels were not reduced. The onset and development of atherosclerosis was likely delayed by short-term (one to ten weeks) treatment effects, such as increased fecal excretion of neutral sterols, reduced intestinal cholesterol absorption and reduced plasma cholesterol levels, which were not significant after long-term (20 weeks) treatment. Increased HDL-cholesterol and reducedintestinal cholesterol absorption may lead to improved ...