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Atherosclerosis/Lipoproteins

Hepatic Cholesterol Homeostasis

Is the Low-Density Lipoprotein Pathway a Regulatory or a Shunt Pathway?

Allan D. Sniderman, Yanqin Qi, Cheng-I J. Ma, Rui Hao Leo Wang, Mark Naples, Chris Baker, Jing Zhang, Khosrow Adeli, Robert S. Kiss
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https://doi.org/10.1161/ATVBAHA.113.301517
Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;ATVBAHA.113.301517
Originally published August 29, 2013
Allan D. Sniderman
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.).
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Yanqin Qi
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.).
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Cheng-I J. Ma
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.).
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Rui Hao Leo Wang
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.).
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Mark Naples
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.).
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Chris Baker
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.).
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Jing Zhang
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.).
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Khosrow Adeli
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.).
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Robert S. Kiss
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.).
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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 very-LDL. 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 very-LDL 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 very-LDL particles without reaching equilibrium with the regulatory pool.

  • cholesterol
  • 3-hydroxy-3-methylglutaryl-coenzyme A
  • high-density lipoproteins
  • sterol O-acyltransferase
  • very–low-density lipoproteins
  • Received August 25, 2012.
  • Accepted August 13, 2013.
  • © 2013 American Heart Association, Inc.
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    Hepatic Cholesterol Homeostasis
    Allan D. Sniderman, Yanqin Qi, Cheng-I J. Ma, Rui Hao Leo Wang, Mark Naples, Chris Baker, Jing Zhang, Khosrow Adeli and Robert S. Kiss
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;ATVBAHA.113.301517, originally published August 29, 2013
    https://doi.org/10.1161/ATVBAHA.113.301517

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    Hepatic Cholesterol Homeostasis
    Allan D. Sniderman, Yanqin Qi, Cheng-I J. Ma, Rui Hao Leo Wang, Mark Naples, Chris Baker, Jing Zhang, Khosrow Adeli and Robert S. Kiss
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;ATVBAHA.113.301517, originally published August 29, 2013
    https://doi.org/10.1161/ATVBAHA.113.301517
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