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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1298.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Coexpression of CLA-1 and Human PDZK1 in Murine Liver Modulates HDL Cholesterol Metabolism

Hidenori Komori; Hidenori Arai; Terumi Kashima; Thierry Huby; Toru Kita; Yukihiko Ueda

From the Departments of Cardiovascular Medicine (H.K., T.K., Y.U.) and Geriatric Medicine (H.A.), Kyoto University Graduate School of Medicine, Japan; Shiga Medical Center Research Institute (T.K.), Moriyama, Japan; and INSERM U551 (T.H.), Dyslipoproteinemia and Atherosclerosis Research Unit, Hôpital de la Pitié, Paris, France. Present address for Y.U.: Kei-Han-Na Hospital, Hirakata, Japan.

Correspondence to Hidenori Arai, MD, PhD, Department of Geriatric Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. E-mail harai{at}kuhp.kyoto-u.ac.jp

Objective— In rodents scavenger receptor class B type I (SR-BI) is a key molecule for selective uptake of cholesteryl ester from high-density lipoprotein (HDL). This study was aimed to clarify the role of the human SR-BI/CD36 and LIMP-II Analogues-1 (CLA-1) as a molecular target of selective uptake of cholesteryl ester from HDL in vivo.

Methods and Results— To clarify the function and regulation of CLA-1 in vivo we produced CLA-1 BAC transgenic mice. In spite of abundant hepatic RNA expression of CLA-1, CLA-1 BAC transgenic mice had no significant effect on mouse HDL cholesterol. Although coexpression of a human scaffolding protein PDZK1 along with CLA-1 enhanced hepatic CLA-1 expression, it did not affect mouse HDL cholesterol levels, either. However, in the presence of human apoA-1, HDL cholesterol level and size were significantly reduced in CLA-1 transgenic mice, and its reduction was more pronounced in CLA-1/human PDZK1 double transgenic mouse.

Conclusions— We established a mouse model to study human reverse cholesterol transport by expressing CLA-1, human PDZK1, and human apoA-I gene. Our results imply that enhancing CLA-1 expression by human PDZK1 in the liver can modulate HDL cholesterol metabolism and possibly enhance reverse cholesterol transport to prevent the progression of atherosclerosis in human.

Transgenic expression of human PDZK1 increased hepatic CLA-1 expression in murine liver. Enhanced hepatic CLA-1 expression increased the clearance of HDL particles containing human apoA-I. Thus CLA-1 and human PDZK1 have a potential to modulate HDL cholesterol metabolism in human.

Key Words: lipoproteins • receptor • transgenic model • apolipoproteins • genetically altered mice