Hypertriglyceridemia in Lecithin-cholesterol Acyltransferase-deficient Mice Is Associated with Hepatic Overproduction of Triglycerides, Increased Lipogenesis, and Improved Glucose Tolerance

Ng, Dominic S.; Xie, Chuncheng; Maguire, Graham F.; Zhu, X.F.; Ugwu, Francisca; Lam, Eric Chen Quin; Connelly, Philip W.

doi:10.1074/jbc.m309439200

Cited by 39 publications

(43 citation statements)

References 62 publications

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“…4A), suggesting that CBS Ϫ/Ϫ mice may be susceptible to atherosclerosis. Intravascular VLDL lipolysis is regulated by LPL, which is activated by hepatic LCAT secreted into blood vessels (23,38). In the present study, we found that the lcat expression and LCAT activity were significantly decreased in CBS Ϫ/Ϫ mouse liver and serum, respectively (Fig.…”

Section: Fig 3 Apob100 Contents/distribution In Serum (Lipoproteinssupporting

confidence: 61%

“…matrix-assisted laser desorption ionization mass spectrometry), which will be pursued in the future studies. It has been shown that LCAT-deficient mice have the decreased levels of esterified and HDL-cholesterol as well as increased levels of TG and free cholesterol (23,30,41), features that were also observed in our CBS-deficient mice. Therefore, CBS Ϫ/Ϫ mice may have increased TG production from the liver caused by LCAT deficiency, resulting in the development of hepatic steatosis (23).…”

Section: Fig 3 Apob100 Contents/distribution In Serum (Lipoproteinssupporting

confidence: 51%

“…LPL hydrolysis of VLDL was measured as described previously (23,24) with some modifications. Briefly, serum samples were incubated with purified bovine LPL (0.2 mg/ml) in 100 mM Tris (pH 8.5) at 37°C for 10 min.…”

Section: Lipolysis By Lplmentioning

confidence: 99%

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Abnormal Lipid Metabolism in Cystathionine β-Synthase-deficient Mice, an Animal Model for Hyperhomocysteinemia

Namekata

Enokido

Ishii

et al. 2004

Journal of Biological Chemistry

136

135

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Hyperhomocysteinemia (HHCY) is a consequence of impaired methionine/cysteine metabolism and is caused by deficiency of vitamins and/or enzymes such as cystathionine ␤-synthase (CBS). Although HHCY is an important and independent risk factor for cardiovascular diseases that are commonly associated with hepatic steatosis, the mechanism by which homocysteine promotes the development of fatty liver is poorly understood. CBS-deficient (CBS ؊/؊ ) mice were previously generated by targeted deletion of the Cbs gene and exhibit pathological features similar to HHCY patients, including endothelial dysfunction and hepatic steatosis. Here we show abnormal lipid metabolism in CBS ؊/؊ mice. Triglyceride and nonesterified fatty acid levels were markedly elevated in CBS ؊/؊ mouse liver and serum. The activity of thiolase, a key enzyme in ␤-oxidation of fatty acids, was significantly impaired in CBS ؊/؊ mouse liver. Hepatic apolipoprotein B100 levels were decreased, whereas serum apolipoprotein B100 and very low density lipoprotein levels were elevated in CBS ؊/؊ mice. Serum levels of cholesterol/ phospholipid in high density lipoprotein fractions but not of total cholesterol/phospholipid were decreased, and the activity of lecithin-cholesterol acyltransferase was severely impaired in CBS ؊/؊ mice. Abnormal high density lipoprotein particles with higher mobility in polyacrylamide gel electrophoresis were observed in serum obtained from CBS ؊/؊ mice. Moreover, serum cholesterol/ triglyceride distribution in lipoprotein fractions was altered in CBS ؊/؊ mice. These results suggest that hepatic steatosis in CBS ؊/؊ mice is caused by or associated with abnormal lipid metabolism.

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Section: Fig 3 Apob100 Contents/distribution In Serum (Lipoproteinssupporting

confidence: 61%

Section: Fig 3 Apob100 Contents/distribution In Serum (Lipoproteinssupporting

confidence: 51%

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Abnormal Lipid Metabolism in Cystathionine β-Synthase-deficient Mice, an Animal Model for Hyperhomocysteinemia

Namekata

Enokido

Ishii

et al. 2004

Journal of Biological Chemistry

136

135

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“…In the current study we observed that LCAT KO mice that completely lack HDL-cholesteryl esters also display diminished glucocorticoid signaling in hepatocytes because they exhibit a lowered hepatic APOA4 mRNA expression level and a compensatory up-regulation of liver corticosteroid binding globulin expression. In line with a generally lower hepatic glucocorticoid signaling in LCAT KO mice, Ng et al ( 29 ) have previously detected a lower relative expression level of the glucocorticoid-responsive gene PEPCK and a parallel decrease in plasma glucose levels in response to LCAT defi ciency. In contrast to the change in hepatic glucocorticoid action in LCAT KO mice, leukocyte-specifi c glucocorticoid signaling is apparently normal in these mice because the susceptibility to endotoxemia is unaffected.…”

Section: Discussionmentioning

confidence: 96%

LCAT deficiency in mice is associated with a diminished adrenal glucocorticoid function

Hoekstra¹,

Korporaal

Sluis³

et al. 2013

Journal of Lipid Research

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The production and subsequent secretion of glucocorticoids by adrenocortical cells of the zona fasciculata is dependent on the availability of the steroidogenic precursor cholesterol. Unesterifi ed cholesterol is converted to glucocorticoids through a series of side-chain modifi cations by cytochrome P450 enzymes and hydroxysteroid dehydrogenases ( 1 ). The intramitochondrial transfer of unesterifi ed cholesterol by the enzyme steroidogenic acute regulatory protein is considered to be the rate-limiting step in the basal synthesis of glucocorticoids. In vitro studies using isolated adrenocortical cells have suggested that HDL and apoBcontaining lipoproteins are able to provide cholesterol as source for the synthesis of glucocorticoids ( 2-5 ). We and others have shown that under conditions where glucocorticoids are physiologically relevant (i.e., under stress), the exogenous uptake and intracellular processing of lipoprotein-associated cholesteryl esters becomes of crucial importance to maintain optimal adrenal glucocorticoid function in vivo. Probucol-induced depletion of plasma cholesterol associated with HDL and LDL in C57BL/6 wild-type mice is associated with a lower stress-induced glucocorticoid level ( 6 ). In addition, a defect in the hydrolysis of lipoproteinassociated cholesteryl esters in hormone-sensitive lipase knockout (KO) mice is associated with adrenocortical hypofunction ( 7 ). Furthermore, apolipoprotein A1 (APOA1) KO mice that virtually lack HDL particles and scavenger receptor BI (SR-BI) KO mice that exhibit an impaired uptake of cholesteryl esters from HDL show a parallel diminished adrenal glucocorticoid function ( 8-10 ). Combined, these fi ndings suggest that the uptake of HDL-cholesteryl esters by the adrenals is essential to maintain optimal glucocorticoid production in vivo.Abstract In vitro studies have suggested that HDL and apoB-containing lipoproteins can provide cholesterol for synthesis of glucocorticoids. Here we assessed adrenal glucocorticoid function in LCAT knockout (KO) mice to determine the specifi c contribution of HDL-cholesteryl esters to adrenal glucocorticoid output in vivo. LCAT KO mice exhibit an 8-fold higher plasma free cholesterol-to-cholesteryl ester ratio ( P < 0.001) and complete HDL-cholesteryl ester defi ciency. ApoB-containing lipoprotein and associated triglyceride levels are increased in LCAT KO mice as compared with C57BL/6 control mice (44%; P < 0.05). Glucocorticoidproducing adrenocortical cells within the zona fasciculata in LCAT KO mice are devoid of neutral lipids. However, adrenal weights and basal corticosterone levels are not significantly changed in LCAT KO mice. In contrast, adrenals of LCAT KO mice show compensatory up-regulation of genes involved in cholesterol synthesis (HMG-CoA reductase; 516%; P < 0.001) and acquisition (LDL receptor; 385%; P < 0.001) and a marked 40-50% lower glucocorticoid response to adrenocorticotropic hormone exposure, endotoxemia, or fasting ( P < 0.001 for all). In conclusion, our studies show that HDL-cholesteryl es...

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“…This is further supported by the previous reports of the presence of LCAT activities directly on the non-HDL particles. When LDL receptor knockout mice and apoE knockout mice, both characterized by severe hyperlipidemia caused by defective clearance of apoBcontaining particles, develop plasma accumulation of LpX when made LCAT deficient, 15,27 but only to a relatively minor degree. By contrast, the SϩlcatϪ/Ϫ mice showed marked increase in circulating LpX despite being hypolipidemic, further attesting to the importance of Deposits are qualitatively much fewer in number than in SϩlcatϪ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

A Novel in Vivo Lecithin-Cholesterol Acyltransferase (LCAT)-Deficient Mouse Expressing Predominantly LpX Is Associated with Spontaneous Glomerulopathy

Zhu

Herzenberg

Eskandarian

et al. 2004

The American Journal of Pathology

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Complete lecithin cholesterol acyltransferase (LCAT) deficiency is a rare genetic cause of extreme reduction in high density lipoproteins and there is a high prevalence of chronic renal dysfunction that may progress to renal failure. Previous in vitro studies suggest the vesicular lipoprotein X (LpX) particles commonly seen in LCAT-deficient plasmas may be causative. To test this hypothesis, we have generated a novel murine model that selectively accumulate LpX in the circulation by cross breeding the sterol regulatory element binding protein (SREBP) 1a transgenic mice (S؉) with the LCAT knockout (lcat؊/؊) mice. Lecithin cholesterol acyltransferase (LCAT) deficiency is a rare monogenic disorder causative of severe plasma high density lipoprotein (HDL) deficiency. It has been well established that LCAT mediates the transfer of the sn-2 fatty acyl moiety in phosphatidylcholine (PC) to the hydroxyl group of cholesterol. This reaction occurs predominantly on the HDL particles but significant LCAT activity has also been documented in non-HDL lipoprotein particles. 1,2 This reaction is central to the reverse cholesterol transport pathway in HDL metabolism 3 and a deficiency of the enzyme activity results in a reduction in plasma HDL-cholesterol (HDL-C) levels in a concentration-dependent manner. The residual plasma HDL is characterized by an accumulation of disk-shaped pre␤ HDL that may form the characteristic rouleaux on electron microscopy. 4,5 Other lipid phenotypes include an increase in plasma free cholesterol to esterified cholesterol (FC/CE) ratio, modest fasting hypertriglyceridemia, morphologically abnormal low density lipoprotein (LDL) and very low density lipoprotein (VLDL) particles and the formation of FC-and phospholipid (PL)-rich but triglyceride-poor vesicles known as lipoprotein X (LpX). 4,6 These vesicles, with the buoyant density in the LDL range but

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Hypertriglyceridemia in Lecithin-cholesterol Acyltransferase-deficient Mice Is Associated with Hepatic Overproduction of Triglycerides, Increased Lipogenesis, and Improved Glucose Tolerance

Cited by 39 publications

References 62 publications

Abnormal Lipid Metabolism in Cystathionine β-Synthase-deficient Mice, an Animal Model for Hyperhomocysteinemia

Abnormal Lipid Metabolism in Cystathionine β-Synthase-deficient Mice, an Animal Model for Hyperhomocysteinemia

LCAT deficiency in mice is associated with a diminished adrenal glucocorticoid function

A Novel in Vivo Lecithin-Cholesterol Acyltransferase (LCAT)-Deficient Mouse Expressing Predominantly LpX Is Associated with Spontaneous Glomerulopathy

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