Allan D Sniderman1, Yanqin Qi, Cheng-I J Ma, Rui Hao Leo Wang, Mark Naples, Chris Baker, Jing Zhang, Khosrow Adeli, Robert S Kiss. 1. From the Department of Medicine, Cardiovascular Research Laboratories, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada (A.D.S., Y.Q., C.J.M., R.H.L.W., R.S.K.); Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (M.N., C.B., J.Z., K.A.); and Department of Biochemistry and Laboratory Medicine, University of Toronto, Toronto, Ontario, Canada (M.N., C.B., J.Z., K.A.).
Abstract
OBJECTIVE: The hypothesis that cholesterol that enters the cell within low-density lipoprotein (LDL) particles rapidly equilibrates with the regulatory pool of intracellular cholesterol and maintains cholesterol homeostasis by reducing cholesterol and LDL receptor synthesis was validated in the fibroblast but not in the hepatocyte. Accordingly, the present studies were designed to compare the effects of cholesterol that enters the hepatocyte within an LDL particle with those of cholesterol that enters via other lipoprotein particles. APPROACH AND RESULTS: We measured cholesterol synthesis and esterification in hamster hepatocytes treated with LDL and other lipoprotein particles, including chylomicron remnants and VLDL. Endogenous cholesterol synthesis was not significantly reduced by uptake of LDL, but cholesterol esterification (280%) and acyl CoA:cholesterol acyltransferase 2 expression (870%) were increased. In contrast, cholesterol synthesis was significantly reduced (70% decrease) with other lipoprotein particles. Furthermore, more cholesterol that entered the hepatocyte within LDL particles was secreted within VLDL particles (480%) compared with cholesterol from other sources. CONCLUSIONS: Much of the cholesterol that enters the hepatocyte within LDL particles is shunted through the cell and resecreted within VLDL particles without reaching equilibrium with the regulatory pool.
OBJECTIVE: The hypothesis that cholesterol that enters the cell within low-density lipoprotein (LDL) particles rapidly equilibrates with the regulatory pool of intracellular cholesterol and maintains cholesterol homeostasis by reducing cholesterol and LDL receptor synthesis was validated in the fibroblast but not in the hepatocyte. Accordingly, the present studies were designed to compare the effects of cholesterol that enters the hepatocyte within an LDL particle with those of cholesterol that enters via other lipoprotein particles. APPROACH AND RESULTS: We measured cholesterol synthesis and esterification in hamster hepatocytes treated with LDL and other lipoprotein particles, including chylomicron remnants and VLDL. Endogenous cholesterol synthesis was not significantly reduced by uptake of LDL, but cholesterol esterification (280%) and acyl CoA:cholesterol acyltransferase 2 expression (870%) were increased. In contrast, cholesterol synthesis was significantly reduced (70% decrease) with other lipoprotein particles. Furthermore, more cholesterol that entered the hepatocyte within LDL particles was secreted within VLDL particles (480%) compared with cholesterol from other sources. CONCLUSIONS: Much of the cholesterol that enters the hepatocyte within LDL particles is shunted through the cell and resecreted within VLDL particles without reaching equilibrium with the regulatory pool.
Authors: Daniel Oropeza; Nathalie Jouvet; Khalil Bouyakdan; Gabrielle Perron; Lea-Jeanne Ringuette; Louis H Philipson; Robert S Kiss; Vincent Poitout; Thierry Alquier; Jennifer L Estall Journal: Mol Metab Date: 2015-08-14 Impact factor: 7.422