Expression of Human ApoAII in Transgenic Rabbits Leads to Dyslipidemia

Abstract

Objective-Apolipoprotein AII (apoAII) is the second major apolipoprotein in high-density lipoprotein (HDL). However, the physiological functions of apoAII in lipoprotein metabolism have not been fully elucidated. Methods and Results-We generated human apoAII transgenic (Tg) rabbits, a species that normally does not have an endogenous apoAII gene. Plasma levels of human apoAII in Tg rabbits were Ϸ30 mg/dL, similar to the plasma levels in healthy humans. The expression of human apoAII in Tg rabbits resulted in increased levels of plasma triglycerides, total cholesterol, and phospholipids accompanied by a marked reduction in HDL-cholesterol levels compared with non-Tg littermates. Analysis of lipoprotein fractions showed that hyperlipidemia exhibited by Tg rabbits was caused by elevated levels of very-low-density lipoproteins ( Key Words: apolipoprotein Ⅲ lipase Ⅲ transgenic rabbits Ⅲ hyperlipidemia Ⅲ HDL H igh levels of plasma high-density lipoproteins (HDL) are associated with a low incidence of cardiovascular disease. 1 HDL contains 2 major apolipoproteins (apo): apoAI and apoAII. It is generally accepted that apoAI plays a central role in reverse cholesterol transport and protects against atherosclerosis 2,3 ; however, apoAII functions have not been clearly characterized. 4 -6 See accompanying article on page 1984Clinical and epidemiological studies have yielded conflicting results regarding the relationship between plasma apoAII levels and coronary heart disease: apoAII is either proatherogenic 7 or atheroprotective. 8 The Ϫ265C polymorphism in the apoAII promoter region was shown to be associated with decreased plasma apoAII concentration and enhance postprandial metabolism of large very-low-density lipoproteins (VLDL). 9 Nevertheless, apoAII has long been considered to be of physiologically minor importance in lipoprotein metabolism because apoAII deficiency is not associated with a high susceptibility to coronary heart disease. 10 ApoAII transgenic (Tg) mice along with knock-out (KO) mice have revealed multiple functions of apoAII. 4,5 Both human and mouse apoAII in Tg mice are involved in VLDL metabolism, but mouse apoAII is also associated with obesity and insulin resistance. [11][12][13] In addition, mouse apoAII is proatherogenic in chow-fed Tg mice, whereas human apoAII is either atheroprotective or proatherogenic in Tg mice dependent on an atherogenic diet. 14 -17 Although the cause of these discrepancies in different mice expressing different transgenes is unclear, it seems that there is a species difference in apoAII functions between human and mouse, and that the precise physiological functions of apoAII in vivo remain to be elucidated. Studies using Tg mice are often complicated by additional factors such as the effect of human homodimer apoAII versus murine monomer apoAII, transgenic apoAII (either human or murine) versus endogenous murine apoAII,

ApoA-I deficiency in mice is associated with redistribution of apoA-II and aggravated AApoAII amyloidosis

“…ApoA-II, the second most abundant protein present in human, mouse, rat, and fi sh plasma HDL ( 11 ), was long considered to be of minor physiologically importance in lipoprotein metabolism because apoA-II defi ciency is not associated with a high susceptibility to coronary heart disease ( 12 ). However, recent studies show that apoA-II plays multiple metabolic roles in maintaining the plasma HDL pool (13)(14)(15), promoting obesity and insulin resistance ( 15,16 ), augmenting monocyte responses to lipopolysaccharides (LPS) ( 17 ), and decreasing triglyceride catabolism, mainly by impairing lipoprotein lipase (LPL) activity ( 13 ). Although human apoA-II is either atheroprotective or pro-atherogenic in transgenic mice, depending on an atherogenic diet ( 18 ), mouse apoA-II is pro-atherogenic in chow-fed transgenic mice ( 19 ).…”

Genetically Modified Animal Models for Lipoprotein Research

“…Therefore, the function of apoA-II is very confusing in mouse models. Conversely, rabbits overexpressing human apoA-II, which do not have apoA-II, lipid levels in plasma and non-HDL lipoproteins were increased but HDL-cholesterol levels and activities of LPL and HL were decreased (Koike, 2009). Therefore, effects of human apoA-II overexpression may be different between mice and rabbits.…”

“…Knockout animals mouse rat rabbit mouse rat chick Apolipoprotein apoA- I Walsh, 1989Swanson, 1992Duverger, 1996Plump, 1997apoA-II Marzal-Casacub, 1996Koike, 2009Weng, 1996apoB100 Farese, 1995Fan, 1995apoC-I Simonet, 1991Gautier, 2002apoC-II Shachter, 1994apoC-III Aalto-Setala, 1992 Ding, 2011 apoC-IV Allan, 1996apoE Shimano, 1992Fan, 1998 LPL Shimada, 1993Fan, 2001Coleman, 1995HL Braschi, 1998Fan, 1994Gonzalez-Navarro, 2004EL Ishida, 2003Ishida, 2003;Ma, 2003 Lipoprotein metabolism LDLR Hofmann, 1998Ishibashi, 1993Asahina, 2012PCSK9 Herbert, 2010Rashid, 2005VLDLR Frykman, 1995 Rigotti, 1997LCAT Vaisman, 1995CETP Aggellon, 1991Herrera, 1999PLTP Jiang, 1996Masson, 2011Jiang, 1999 …”

“…One contains only apoA-I and the other, both apoA-I and apoA-II. However, rabbit HDLs are apoA-I particles (Chapman, 1980& Koike, 2009). ApoA-I plays an important role in the reverse transport of cholesterol.…”

“…These lipolytic products are translocated to the enterocyte membrane, and migrate to the endoplasmic reticulum. Overexpression of the tis7 gene in mice increases triglyceride absorption (Wang, 2009), and the transport of saturated fatty acids and cholesterol is decreased in fatty acid-binding protein (FABP)-KO mice (Newberry, 2009). Monoglycerides and fatty acids are re-esterified into triglycerides at the cytoplasmic surface of the endoplasmic reticulum.…”