Altered hepatic cholesterol metabolism compensates for disruption of phosphatidylcholine transfer protein in mice

2005 ◽  
Vol 289 (3) ◽  
pp. G456-G461 ◽  
Author(s):  
Michele K. Wu ◽  
David E. Cohen
Keyword(s):  
Cholesterol Metabolism ◽  
Hepatic Cholesterol ◽  
Wild Type ◽  
Unesterified Cholesterol ◽  
Hydroxylase Activity ◽  
Lithogenic Diet ◽  
Transfer Protein ◽  
Acat Activity ◽  
Coa Reductase ◽  
Phosphatidylcholine Transfer Protein

Phosphatidylcholine transfer protein (PC-TP) is a member of the steroidogenic acute regulatory transfer protein-related domain superfamily and is enriched in liver. To explore a role for PC-TP in hepatic cholesterol metabolism, Pctp −/− and wild-type C57BL/6J mice were fed a standard chow diet or a high-fat, high-cholesterol lithogenic diet. In chow-fed Pctp−/− mice, acyl CoA:cholesterol acyltransferase (Acat) activity was markedly increased, 3-hydroxy-3-methylglutaryl-CoA reductase activity was unchanged, and cholesterol 7α-hydroxylase activity was reduced. Consistent with increased Acat activity, esterified cholesterol concentrations in livers of Pctp−/− mice were increased, whereas unesterified cholesterol concentrations were reduced. Hepatic phospholipid concentrations were also decreased in the absence of PC-TP and consequently, unesterified cholesterol-to-phospholipid ratios in liver remained unchanged. The lithogenic diet downregulated 3-hydroxy-3-methylglutaryl-CoA reductase in wild-type and Pctp−/− mice, whereas Acat was increased only in wild-type mice. In response to the lithogenic diet, a greater reduction in cholesterol 7α-hydroxylase activity in Pctp−/− mice could be attributed to increased size and hydrophobicity of the bile salt pool. Despite higher hepatic phospholipid concentrations, the unesterified cholesterol-to-phospholipid ratio increased. The lack of Acat upregulation suggests that, in the setting of the dietary challenge, the capacity for esterification to defend against hepatic accumulation of unesterified cholesterol was exceeded in the absence of PC-TP expression. We speculate that regulation of cholesterol homeostasis is a physiological function of PC-TP in liver, which can be overcome with a cholesterol-rich lithogenic diet.

scholarly journals Lithogenic diet and gallstone formation in mice: integrated response of activities of regulatory enzymes in hepatic cholesterol metabolism

1996 ◽  
Vol 76 (5) ◽  
pp. 765-772 ◽  
Author(s):  
Eva Reihnér ◽  
Dagny Ståhlberg
Keyword(s):  
Bile Acids ◽  
Cholic Acid ◽  
Cholesterol Metabolism ◽  
Gallstone Formation ◽  
Hepatic Cholesterol ◽  
Defence Mechanisms ◽  
Cholesterol Acyl Transferase ◽  
Lithogenic Diet ◽  
Acat Activity ◽  
Integrated Response

Supersaturation of bile with cholesterol is a prerequisite of the development of gallstones. With the intention to study the integrated response of enzymes regulating hepatic cholesterol metabolism during gallstone formation we used an established model for the induction of cholesterol gallstone disease in mice. Ten mice were fed on a lithogenic diet containing 10 g cholesterol/kg and 5 g cholic acid/kg for 8 weeks and were compared with ten mice fed on a standard pellet diet. Cholesterol crystals or gallstones developed in 90% of gallbladders in treated mice. The lithogenic diet had an inhibitory effect on the rate-limiting enzyme of cholesterol biosynthesis, hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC1.1.1.88) activity, 39·6 (SEM 2·8)v. 171·0 (SEM 47·3) pmol/min per mg protein. Cholesterol 7α-hydroxylase (EC1.14.13.17) activity, regulating bile acid synthesis, was decreased by 80%, and this was assumed to be due to cholic acid in the diet. The cholesterol-enriched diet also induced a tenfold increase in cholesterol esterification rate in the liver, i.e. acyl-CoA: cholesterol acyl transferase (ACAT;EC2.3.1.26) activity. The total, as well as esterified, cholesterol contents of liver homogenates were significantly higher in cholesterol- and cholic acid-treated mice and correlated well with the ACAT activity (rs0·72 (P < 0·005), and rs0·68 (P < 0·01) respectively). A significantly higher ACAT activity was obtained in mice given cholesterol and cholic acid even when the enzyme was saturated with exogenous cholesterol, thus indicating an increased amount of the enzyme. The formation of gallstones is dependent on a delicate balance between lithogenic factors (increased absorption of cholesterol and reduced secretion of bile acids) and defence mechanisms (decreased synthesis and increased esterification of cholesterol). In the specific animal model studied here the two defence mechanisms cannot compensate for the increased absorption of cholesterol and the reduced synthesis of bile acids.

scholarly journals Phosphatidylcholine transfer protein/StarD2 promotes microvesicular steatosis and liver injury in murine experimental steatohepatitis

2017 ◽  
Vol 313 (1) ◽  
pp. G50-G61 ◽  
Author(s):  
Hayley T. Nicholls ◽  
Jason L. Hornick ◽  
David E. Cohen
Keyword(s):  
Liver Injury ◽  
Lipid Droplets ◽  
Plasma Concentrations ◽  
Fibroblast Growth Factor 21 ◽  
Wild Type ◽  
Hepatocellular Injury ◽  
Pathogenic Role ◽  
Deficient Diet ◽  
Transfer Protein ◽  
Phosphatidylcholine Transfer Protein

Mice fed a methionine- and choline-deficient (MCD) diet develop steatohepatitis that recapitulates key features of nonalcoholic steatohepatitis (NASH) in humans. Phosphatidylcholine is the most abundant phospholipid in the surfactant monolayer that coats and stabilizes lipid droplets within cells, and choline is required for its major biosynthetic pathway. Phosphatidylcholine-transfer protein (PC-TP), which exchanges phosphatidylcholines among membranes, is enriched in hepatocytes. PC-TP also regulates fatty acid metabolism through interactions with thioesterase superfamily member 2. We investigated the contribution of PC-TP to steatohepatitis induced by the MCD diet. Pctp−/− and wild-type control mice were fed the MCD diet for 5 wk and were then euthanized for histopathologic and biochemical analyses, as well as determinations of mRNA and protein expression. Whereas all mice developed steatohepatitis, plasma alanine aminotransferase and aspartate aminotransferase activities were only elevated in wild-type mice, indicating that Pctp−/− mice were protected from MCD diet-induced hepatocellular injury. Reduced hepatotoxicity due to the MCD diet in the absence of PC-TP expression was further evidenced by decreased activation of c-Jun and reduced plasma concentrations of fibroblast growth factor 21. Despite similar total hepatic concentrations of phosphatidylcholines and other lipids, the relative abundance of microvesicular lipid droplets within hepatocytes was reduced in Pctp−/− mice. Considering that the formation of larger lipid droplets may serve to protect against lipotoxicity in NASH, our findings suggest a pathogenic role for PC-TP that could be targeted in the management of this condition. NEW & NOTEWORTHY Phosphatidylcholine-transfer protein (PC-TP) is a highly specific phosphatidylcholine-binding protein that we previously showed to regulate hepatocellular nutrient metabolism through its interacting partner thioesterase superfamily member 2 (Them2). This study identifies a pathogenic role for PC-TP, independent of Them2, in the methionine- and choline-deficient diet model of experimental steatohepatitis. Our current observations suggest that PC-TP promotes liver injury by mediating the intermembrane transfer of phosphatidylcholines, thus stabilizing more pathogenic microvesicular lipid droplets.

scholarly journals Phosphatidylcholine transfer protein regulates size and hepatic uptake of high-density lipoproteins

2005 ◽  
Vol 289 (6) ◽  
pp. G1067-G1074 ◽  
Author(s):  
Michele K. Wu ◽  
David E. Cohen
Keyword(s):  
Plasma Cholesterol ◽  
High Cholesterol Diet ◽  
Atp Binding ◽  
Cholesterol Diet ◽  
Wild Type ◽  
High Cholesterol ◽  
High Fat ◽  
Transfer Protein ◽  
Phosphatidylcholine Transfer Protein ◽  
Atp Binding Cassette

Phosphatidylcholine transfer protein (PC-TP) is a steroidogenic acute regulatory-related transfer domain protein that is enriched in liver cytosol and binds phosphatidylcholines with high specificity. In tissue culture systems, PC-TP promotes ATP-binding cassette protein A1-mediated efflux of cholesterol and phosphatidylcholine molecules as nascent pre-β-high-density lipoprotein (HDL) particles. Here, we explored a role for PC-TP in HDL metabolism in vivo utilizing 8-wk-old male Pctp−/− and wild-type littermate C57BL/6J mice that were fed for 7 days with either chow or a high-fat/high-cholesterol diet. In chow-fed mice, neither plasma cholesterol concentrations nor the concentrations and compositions of plasma phospholipids were influenced by PC-TP expression. However, in Pctp−/− mice, there was an accumulation of small α-migrating HDL particles. This occurred without changes in hepatic expression of ATP-binding cassette protein A1 or in proteins that regulate the intravascular metabolism and clearance of HDL particles. In Pctp−/− mice fed the high-fat/high-cholesterol diet, HDL particle sizes were normalized, whereas plasma cholesterol and phospholipid concentrations were increased compared with wild-type mice. In the absence of upregulation of hepatic ATP-binding cassette protein A1, reduced HDL uptake from plasma into livers of Pctp−/− mice contributed to higher plasma lipid concentrations. These data indicate that PC-TP is not essential for the enrichment of HDL with phosphatidylcholines but that it does modulate particle size and rates of hepatic clearance.

scholarly journals Impaired response of biliary lipid secretion to a lithogenic diet in phosphatidylcholine transfer protein-deficient mice

2004 ◽  
Vol 46 (3) ◽  
pp. 422-431 ◽  
Author(s):  
Michele K. Wu ◽  
Hideyuki Hyogo ◽  
Suresh K. Yadav ◽  
Phyllis M. Novikoff ◽  
David E. Cohen
Keyword(s):  
Biliary Lipid ◽  
Lipid Secretion ◽  
Lithogenic Diet ◽  
Transfer Protein ◽  
Phosphatidylcholine Transfer Protein ◽  
Deficient Mice

scholarly journals Stimulation of hepatic cholesterol biosynthesis by fatty acids. Effects of oleate on cytoplasmic acetoacetyl-CoA thiolase, acetoacetyl-CoA synthetase and hydroxymethylglutaryl-CoA synthase

1989 ◽  
Vol 258 (2) ◽  
pp. 563-568 ◽  
Author(s):  
W H Salam ◽  
H G Wilcox ◽  
L M Cagen ◽  
M Heimberg
Keyword(s):  
Fatty Acids ◽  
Oleic Acid ◽  
Fatty Acid ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Isolated Perfused Rat Liver ◽  
Hepatic Cholesterol ◽  
Hmg Coa Reductase ◽  
Coa Reductase ◽  
Stimulation Of

The effects of oleic acid on the activities of cytosolic HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) synthase, AcAc-CoA (acetoacetyl-CoA) thiolase and AcAc-CoA synthetase, as well as microsomal HMG-CoA reductase, all enzymes in the pathway of cholesterol biosynthesis, were studied in the isolated perfused rat liver. Oleic acid bound to bovine serum albumin, or albumin alone, was infused for 4 h at a rate sufficient to sustain an average concentration of 0.61 +/- 0.05 mM fatty acid during the perfusion. Hepatic cytosol and microsomal fractions were isolated at the termination of the perfusion. Oleic acid simultaneously increased the activities of the cytosolic cholesterol-biosynthetic enzymes 1.4-2.7-fold in livers from normal fed rats and from animals fasted for 24 h. These effects were accompanied by increased net secretion by the liver of cholesterol and triacylglycerol in the very-low-density lipoprotein (VLDL). We confirmed the observations reported previously from this laboratory of the stimulation by oleic acid of microsomal HMG-CoA reductase. In cytosols from perfused livers, the increase in AcAc-CoA thiolase activity was characterized by an increase in Vmax. without any change in the apparent Km of the enzyme for AcAc-CoA. In contrast, oleic acid decreased the Km of HMG-CoA synthase for Ac-CoA, without alteration of the Vmax. of the enzyme. The Vmax. of AcAc-CoA synthetase was increased by oleic acid, and there was a trend towards a small increase in the Km of the enzyme for acetoacetate. These data allow us to conclude that the enzymes that supply the HMG-CoA required for hepatic cholesterogenesis are stimulated, as is HMG-CoA reductase, by a physiological substrate, fatty acid, that increases rates of hepatic cholesterol synthesis and cholesterol secretion. Furthermore, we suggest that these effects of fatty acid on hepatic cholesterol metabolism result from stimulation of secretion of triacylglycerol in the VLDL by fatty acids, and the absolute requirement of cholesterol as an important structural surface component of the VLDL necessary for transport of triacylglycerol from the liver.

Differential regulation of cholesterol homeostasis in transgenic mice expressing human cholesterol ester transfer proteinThis paper is one of a selection of papers published in this Special Issue, entitled The Cellular and Molecular Basis of Cardiovascular Dysfunction, Dhalla 70th Birthday Tribute.

2007 ◽  
Vol 85 (3-4) ◽  
pp. 430-438 ◽  
Author(s):  
Alka Agarwal-Mawal ◽  
Cathy M. Murray ◽  
Suresh Belkhode ◽  
Sukhinder Kaur Cheema
Keyword(s):  
Fatty Acid ◽  
Transgenic Mice ◽  
Cholesterol Ester ◽  
Cholesterol Metabolism ◽  
Cholesterol Homeostasis ◽  
Dietary Fats ◽  
Hmg Coa Reductase ◽  
Transfer Protein ◽  
Coa Reductase ◽  
Mufa Diet

We investigated whether expression of cholesterol ester transfer protein (CETP) in mice alters the regulation of cholesterol metabolism. Transgenic mice expressing human CETP (CETP-TG) and nontransgenic littermates (non-TG) were fed either a monounsaturated fatty acid (MUFA) or a saturated fatty acid (SFA)-rich diet in the presence or absence of cholesterol. Mice fed with MUFA diet had higher CETP activity compared with SFA-fed mice. Addition of cholesterol to the MUFA diet decreased CETP activity, whereas addition of cholesterol to the SFA diet had no effect. Cholesterol 7α-hydroxylase (Cyp7a) activity was higher in CETP-TG mice compared with non-TG mice when fed a MUFA diet, whereas SFA fed CETP-TG mice showed lower Cyp7a activity as compared with non-TG. Microsomal triglyceride transfer protein (MTTP) activity was higher in CETP-TG mice compared with non-TG mice when fed a MUFA diet. HMG-CoA reductase activity was lower in CETP-TG mice compared with non-TG mice when fed a MUFA or a SFA diet. These data demonstrate that the regulation of Cyp7a, HMG-CoA reductase, and MTTP is altered in CETP-TG mice as compared with non-TG mice and these alterations are further modulated by the quality of dietary fats. These findings highlight the importance of CETP in regulating cholesterol homeostasis.

scholarly journals Effect of lovastatin on acyl-CoA: cholesterol O-acyltransferase (ACAT) activity and the basolateral-membrane secretion of newly synthesized lipids by CaCo-2 cells

1990 ◽  
Vol 272 (2) ◽  
pp. 427-433 ◽  
Author(s):  
N T Kam ◽  
E Albright ◽  
S Mathur ◽  
F J Field
Keyword(s):  
Cholesterol Synthesis ◽  
Cholesterol Metabolism ◽  
Reductase Activity ◽  
Basolateral Membrane ◽  
Fatty Acyl ◽  
Intestinal Cell ◽  
Intact Cells ◽  
Hmg Coa Reductase ◽  
Acat Activity ◽  
Coa Reductase

Lovastatin, a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity, was used to study the regulation of cholesterol metabolism and the basolateral-membrane secretion of triacylglycerol and cholesterol in the human intestinal cell line CaCo-2. At 0.1 microgram/ml, lovastatin decreased 3H2O incorporation into cholesterol by 71%. In membranes prepared from cells incubated with lovastatin for 18 h, HMG-CoA reductase activity was induced 4-8-fold. Mevalonolactone prevented this induction. In intact cells, lovastatin (10 micrograms/ml) decreased cholesterol esterification by 50%. The reductase inhibitor decreased membrane acyl-CoA:cholesterol O-acyltransferase (ACAT) activity by 50% at 5 micrograms/ml. ACAT inhibition by lavastatin was not reversed by adding excess of cholesterol or fatty acyl-CoA to the assay. Lovastatin, in the presence or absence of mevalonolactone, decreased the basolateral secretion of newly synthesized cholesteryl esters and triacylglycerols. Lovastatin also inhibited the esterification of absorbed cholesterol and the secretion of this newly synthesized cholesteryl ester. Lovastatin is a potent inhibitor of cholesterol synthesis in CaCo-2 cells. Moreover, it is a direct inhibitor of ACAT activity, independently of its effect on HMG-CoA reductase and cholesterol synthesis.

scholarly journals Intracerebroventricular leptin regulates hepatic cholesterol metabolism

2004 ◽  
Vol 379 (2) ◽  
pp. 229-233 ◽  
Author(s):  
Sonya VanPATTEN ◽  
George B. KARKANIAS ◽  
Luciano ROSSETTI ◽  
David E. COHEN
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Low Dose ◽  
Cholesterol Metabolism ◽  
Hepatic Cholesterol ◽  
The Central Nervous System ◽  
Coa Reductase

To elucidate the control of hepatic cholesterol metabolism by leptin, rats were administered IV (intravenous) leptin, ICV (intracerebroventricular) leptin or saline. A single low dose of ICV leptin was as effective as a continuous IV infusion of highdose leptin at decreasing the activities of 3-hydroxy-3-methylglutaryl-CoA reductase and cholesterol 7α-hydroxylase. These results indicate that the hepatic response to leptin is transduced via the central nervous system.

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