Pituitary regulation of plasma lipoprotein metabolism and intestinal cholesterol absorption

Sammanfattning: Increased levels of plasma cholesterol are associated with a higher risk to develop atherosclerosis, the leading cause of death in Western societies. The major part of cholesterol in human blood is transported within low-density lipoproteins (LDL-C) that bind to specific cell surface receptors (LDLRs). The liver plays a central role in cholesterol metabolism, regulation of LDLRs, and in the de novo synthesis and degradation of cholesterol. The excretion of cholesterol and bile acids from the liver is the major route for elimination of cholesterol from the body. The pituitary exerts important regulatory effects on cholesterol metabolism and the hypophysectomized (Hx) rat constitutes a valuable model to study this regulation. Hx rats show severely altered basal cholesterol metabolism (increased LDL-C, reduced HDL-C, suppressed LDLR and cholesterol 7alphahydroxylase, CYP7A1), concomitant with a striking loss of resistance to dietary cholesterol. Growth hormone (GH) substitution partly normalizes lipid metabolism of Hx rats but the cause for the lost resistance to dietary cholesterol in Hx rats is still unclear. In this thesis, the role of the pituitary in the regulation of hepatic cholesterol metabolism has been further explored. The main findings are: 1) Human GH (hGH) can bind to GH receptors (GHRs) and to prolactin receptors (PRLRs), which are both abundant in the liver. It is demonstrated that the PRLR is not involved in the GH-elicited effects on lipid metabolism of rats; PRL directly administered to Hx rats does not alter the lipid metabolism of Hx rats, and GHs from different species are suitable for research in this field. 2) The Hx mouse is shown to be a novel tool for studies on the role of the pituitary in lipid metabolism. The lipid profiles of Hx mice from 3 strains and the LDLR deficient-Hx mouse model have been characterized. The suppression of LDLRs and CYP7A l in Hx mice cannot fully explain the increased sensitivity to cholesterol feeding following Hx. 3) Cholesterol absorption is strongly increased in Hx rats and can be normalized by treatment with ezetimibe. 4) Plasma cholesterol increases in old rats and humans. However, intestinal cholesterol absorption is unaltered in old rats, and treatment with GH does not affect it. In summary, the lactogenic binding of hGH does not affect lipid metabolism of rats. Compared to the Hx rat, the Hx mouse model shows qualitatively similar but less pronounced metabolic aberrations. Cholesterol absorption is under pituitary control in rats, and the increased intestinal absorption of cholesterol in Hx rats may be the cause for the higher sensitivity to dietary cholesterol following Hx of rats. This study further highlights and extends the role of the pituitary in lipid metabolism in vivo, and shows that a most important pituitary control is exerted on intestinal cholesterol absorption.