Combined hyperlipidemia in transgenic mice overexpressing human apolipoprotein Cl.

Shachter, Neil S.; Ebara, Tetsu; Ramakrishnan, R; Steiner, George; Breslow, Jan L.; Ginsberg, H.S.; Smith, Jonathan

doi:10.1172/jci118857

Cited by 107 publications

(102 citation statements)

References 59 publications

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“…Most of the previous transgenic models of hypertriglyceridemia were characterized by a decreased uptake of remnants of TG-rich lipoproteins, highlighting the role of the balance of apoCs to apoE in the remnant particle for efficient clearance (42)(43)(44)(45). To our knowledge, the only mouse model that fits in an inverse fashion our hypertriglyceridemic mice overexpressing human apoA-II is the apoA-II knockout model.…”

Section: Fig 7 Inhibition Of Lpl and Hl Activities By Human Apoa-iimentioning

confidence: 99%

Overexpression of Human Apolipoprotein A-II in Mice Induces Hypertriglyceridemia Due to Defective Very Low Density Lipoprotein Hydrolysis

Boisfer¹,

Lambert²,

Atger³

et al. 1999

Journal of Biological Chemistry

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Two lines of transgenic mice, hAIItg-␦ and hAIItg-, expressing human apolipoprotein (apo)A-II at 2 and 4 times the normal concentration, respectively, displayed on standard chow postprandial chylomicronemia, large quantities of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) but greatly reduced high density lipoprotein (HDL). Hypertriglyceridemia may result from increased VLDL production, decreased VLDL catabolism, or both. Post-Triton VLDL production was comparable in transgenic and control mice. Postheparin lipoprotein lipase (LPL) and hepatic lipase activities decreased at most by 30% in transgenic mice, whereas adipose tissue and muscle LPL activities were unaffected, indicating normal LPL synthesis. However, VLDL-triglyceride hydrolysis by exogenous LPL was considerably slower in transgenic compared with control mice, with the apparent V max of the reaction decreasing proportionately to human apoA-II expression. Human apoA-II was present in appreciable amounts in the VLDL of transgenic mice, which also carried apoC-II. The addition of purified apoA-II in postheparin plasma from control mice induced a dose-dependent decrease in LPL and hepatic lipase activities. In conclusion, overexpression of human apoA-II in transgenic mice induced the proatherogenic lipoprotein profile of low plasma HDL and postprandial hypertriglyceridemia because of decreased VLDL catabolism by LPL. Low plasma HDL1 levels are negatively correlated with the risk of atherosclerosis. Although a number of metabolic functions of HDL have been identified, no direct link has been established between HDL functions and its antiatherogenic effect (1). In vitro studies have shown that apolipoprotein (apo)A-I, the major HDL apolipoprotein, activates reverse cholesterol transport from extrahepatic tissues to the liver (2). However, conflicting results have been reported concerning the role of apoA-II, the second most abundant HDL apolipoprotein (3, 4). Studies of transgenic mice overexpressing human apoA-I and apoA-II reported that apoA-I protected more against aortic lesions than apoA-II (3). Furthermore, HDL from transgenic mice overexpressing mouse apoA-II lost the ability of HDL to protect against low density lipoprotein (LDL) oxidation (5) and was even proinflammatory (6). Deficiency of either apoA-I (7, 8) or apoA-II (9) obtained by gene targeting technology resulted in very low plasma HDL, showing the critical importance of both apolipoproteins in maintaining the normal structure and metabolism of HDL. At present, apoA-II has been linked with HDL metabolism only, but its exact role remains to be elucidated.Studies of transgenic mice expressing human (10 -13) or murine (14, 15) apoA-II, alone or in combination with human apoA-I, apoC-III, and cholesterol ester transfer protein (16), have provided interesting information. When human apoA-II was expressed at normal levels, overall lipoprotein metabolism was not markedly modified, except for the appearance of a smaller HDL population containing solely human apoA-II (10). At...

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Section: Fig 7 Inhibition Of Lpl and Hl Activities By Human Apoa-iimentioning

confidence: 99%

Overexpression of Human Apolipoprotein A-II in Mice Induces Hypertriglyceridemia Due to Defective Very Low Density Lipoprotein Hydrolysis

Boisfer¹,

Lambert²,

Atger³

et al. 1999

Journal of Biological Chemistry

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show abstract

“…Like apoC-III, apoC-I inhibits remnant clearance and lipoprotein-binding to receptors (16), whereas lipoprotein association to glycosaminoglycans was reported to be unaffected by apoC-I (21). The increased lipid levels in blood of apoC-I transgenic animals were concluded to be due to impaired uptake of VLDL by the liver rather than to an enhanced production or disturbed lipolysis of VLDL (22).…”

mentioning

confidence: 99%

Apolipoproteins C-I and C-III Inhibit Lipoprotein Lipase Activity by Displacement of the Enzyme from Lipid Droplets

Larsson

Vorrsjö

Talmud

et al. 2013

Journal of Biological Chemistry

145

128

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Background: Apolipoproteins (apo) C-I and C-III regulate plasma triglyceride metabolism by inhibition of lipoprotein lipase (LPL) activity. Results: ApoC-I or apoC-III prevents LPL from binding to lipid droplets. This results in inhibition of LPL. Conclusion: Inhibition of LPL activity by apoC-I and apoC-III is due to displacement of LPL from lipid droplets. Significance: Our proposed mechanism explains several effects of these apolipoproteins on lipoprotein metabolism.

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“…[6][7][8] In addition, a negative correlation between LPL activity and levels of apo C-II and apo C-III in plasma have been demonstrated in hypertriglyceridemic patients. 9 Furthermore, in transgenic mice overexpressing either human apo C-I, 10,11 apo C-II, 12 or apo C-III, 13 an accumulation of triglyceride-rich lipoproteins in plasma occurs, which suggests a causal relationship. These observations are mechanistically supported by results from in vitro studies showing that an excess of C apolipoproteins on triglyceride-rich lipoprotein particles interferes with their binding to cell surface receptors and subsequent clearance.…”

mentioning

confidence: 99%

Developmental and Pharmacological Regulation of Apolipoprotein C-II Gene Expression

Andersson

Majd

Lefebvre

et al. 1999

ATVB

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Abstract-Increased plasma triglyceride concentrations are often observed in metabolic disorders predisposing to coronary heart disease. Among the major determinants of plasma triglyceride metabolism are the apolipoproteins (apos) of the C class, C-I, C-II, and C-III. Whereas physiological concentrations of apo C-II are required for lipolysis of triglycerides by lipoprotein lipase (LPL), overexpression of all 3 C apolipoproteins leads to hypertriglyceridemia. In the present study, we investigated apo C-II gene regulation under conditions associated with profound changes in plasma triglyceride metabolism, ie, during postnatal development and after treatment with the triglyceride-lowering fibrate drugs, and compared its expression to that of apo C-I and apo C-III. Whereas the expression of both apo C-I and apo C-III is low in fetal liver, increases gradually after birth, and attains maximal levels after weaning, apo C-II gene expression is already detectable in the fetal liver, increases rapidly immediately after birth, and remains elevated throughout suckling. Thus, the increased ingestion of lipids during suckling is met by an earlier induction of apo C-II, the obligatory activator for LPL, compared with apo C-III and apo C-I, which antagonize triglyceride catabolism. Treatment of rats with fibrates decreased apo C-II gene expression in the liver, but not in the intestine, whereas apo C-I gene expression did not change. The decrease of liver apo C-II mRNA levels after fenofibrate occurred in a time-and dose-dependent manner and was reversible but appeared less pronounced than the decrease of apo C-III mRNA. Apo C-II mRNA levels were not affected after treatment with BRL49653, a peroxisome proliferator-activated receptor (PPAR)␥-specific ligand, suggesting that fibrates act on apo C-II expression via PPAR␣. Addition of fenofibric acid to primary rat and human hepatocytes resulted in a decrease of apo C-II expression. In conclusion, fibrates decrease gene expression of apo C-II and apo C-III, but not apo C-I, in rat and human hepatocytes. This decrease of apo C-II and apo C-III gene expression, together with a lowered apo C-III to apo C-II ratio, should result in an improved clearance of triglyceride-rich remnant lipoproteins from plasma, without hampering triglyceride lipolysis by LPL.

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Combined hyperlipidemia in transgenic mice overexpressing human apolipoprotein Cl.

Abstract: We have generated transgenic mice over-expressing human apolipoprotein CI (apo CI) using the native gene joined to the downstream 154-bp liver-specific enhancer that we defined for apo E. Human apo CI (

Cited by 107 publications

References 59 publications

Overexpression of Human Apolipoprotein A-II in Mice Induces Hypertriglyceridemia Due to Defective Very Low Density Lipoprotein Hydrolysis

Overexpression of Human Apolipoprotein A-II in Mice Induces Hypertriglyceridemia Due to Defective Very Low Density Lipoprotein Hydrolysis

Apolipoproteins C-I and C-III Inhibit Lipoprotein Lipase Activity by Displacement of the Enzyme from Lipid Droplets

Developmental and Pharmacological Regulation of Apolipoprotein C-II Gene Expression

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