ABCA1 Is Essential for Efficient Basolateral Cholesterol Efflux during the Absorption of Dietary Cholesterol in Chickens

Mulligan, Jacob D.; Flowers, Matthew T.; Tebon, Angie; Bitgood, J. J.; Wellington, Cheryl L.; Hayden, Michael R.; Attie, Alan D.

doi:10.1074/jbc.m212377200

Cited by 111 publications

(100 citation statements)

References 72 publications

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“…Plasma lipid analysis. Plasma lipoproteins were fractionated on a Superose 6HR 10/30 FPLC column (Amersham Bioscience) as described (19). The equivalent of 100 l plasma was injected onto the column, and 500-l fractions were collected and assayed for total cholesterol and triglyceride.…”

Section: Methodsmentioning

confidence: 99%

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Loss of Stearoyl-CoA Desaturase-1 Improves Insulin Sensitivity in Lean Mice but Worsens Diabetes in Leptin-Deficient Obese Mice

Flowers

Rabaglia²,

Schueler³

et al. 2007

Diabetes

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134

122

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The lipogenic gene stearoyl-CoA desaturase (SCD)1 appears to be a promising new target for obesity-related diabetes, as mice deficient in this enzyme are resistant to diet-and leptin deficiency-induced obesity. The BTBR mouse strain replicates many features of insulin resistance found in humans with excess visceral adiposity. Using the hyperinsulinemic-euglycemic clamp technique, we determined that insulin sensitivity was improved in heart, soleus muscle, adipose tissue, and liver of BTBR SCD1-deficient mice. We next determined whether SCD1 deficiency could prevent diabetes in leptin-deficient BTBR mice. Loss of SCD1 in leptin ob/ob mice unexpectedly accelerated the progression to severe diabetes; 6-week fasting glucose increased ϳ70%. In response to a glucose challenge, Scd1 Ϫ/Ϫ leptin ob/ob mice had insufficient insulin secretion, resulting in glucose intolerance. A morphologically distinct class of islets isolated from the Scd1 Ϫ/Ϫ leptin ob/ob mice had reduced insulin content and increased triglycerides, free fatty acids, esterified cholesterol, and free cholesterol and also a much higher content of saturated fatty acids. We believe the accumulation of lipid is due to an upregulation of lipoprotein lipase (20-fold) and Cd36 (167-fold) and downregulation of lipid oxidation genes in this class of islets. Therefore, although loss of Scd1 has beneficial effects on adiposity, this benefit may come at the expense of ␤-cells, resulting in an increased risk of diabetes. Diabetes 56:1228-1239, 2007 S tearoyl-CoA desaturase (SCD) catalyzes the synthesis of monounsaturated fatty acids by introducing a cis double bond in the ⌬9 position of saturated 16-and 18-carbon fatty acyl-CoA substrates. The products of SCD, palmitoleoyl-CoA and oleoylCoA, are the most abundant monounsaturated fatty acids of phospholipids, triglycerides, cholesterol esters, and wax esters (1). Various diseases, including cancer, obesity, diabetes, and atherosclerosis, are associated with an imbalance in the ratio of saturated to monounsaturated fatty acids (2). Two human and four mouse isoforms of SCD have been characterized. SCD1 is the primary isoform found in lipogenic tissues.Loss of Scd1 is protective against obesity (3-5). The decreased adiposity in the Scd1 Ϫ/Ϫ mice is due to reduced lipid synthesis and increased energy expenditure through enhanced fatty acid oxidation (3). Scd1 Ϫ/Ϫ mice have an increase in insulin signaling and glucose uptake in muscle and brown adipose tissue (6,7).Leptin-deficient BTBR leptin ob/ob mice are a particularly useful animal model for studying obesity-related diabetes. Unlike the B6 leptin ob/ob mice, which develop only moderate hyperglycemia, BTBR leptin ob/ob mice become severely diabetic (8 -10). The diabetic BTBR leptin ob/ob mice have increased Scd1 expression in muscle and decreased expression in adipose tissue and liver, compared with nondiabetic B6 leptin ob/ob mice (10). Insulin resistance is often correlated with abdominal obesity. The BTBR mouse strain has excess abdominal obesity associated with ins...

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Section: Methodsmentioning

confidence: 99%

“…Fatty acids were then trans-methylated and analyzed by gas liquid chromatography (18). The cholesterol and cholesterol ester bands were scraped, extracted, diluted with 90 l of 10% Triton-X100 in isopropyl alcohol, and measured with the Wako Cholesterol E kit (19). Plasma lipid analysis.…”

Section: Methodsmentioning

confidence: 99%

Loss of Stearoyl-CoA Desaturase-1 Improves Insulin Sensitivity in Lean Mice but Worsens Diabetes in Leptin-Deficient Obese Mice

Flowers

Rabaglia²,

Schueler³

et al. 2007

Diabetes

Self Cite

134

122

View full text Add to dashboard Cite

show abstract

“…In intestinal cells, ABCA1 has been shown to regulate the efflux of cholesterol from the basolateral but not the apical membrane [195]. ABCA1 is expressed only on the basolateral surface of the hepatocytes [196].…”

Section: Abca1 and Hdl Assemblymentioning

confidence: 99%

Recent advances in physiological lipoprotein metabolism

Ramasamy

2014

Clinical Chemistry and Laboratory Medicine (CCLM)

182

159

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Abstract:Research into lipoprotein metabolism has developed because understanding lipoprotein metabolism has important clinical indications. Lipoproteins are risk factors for cardiovascular disease. Recent advances include the identification of factors in the synthesis and secretion of triglyceride rich lipoproteins, chylomicrons (CM) and very low density lipoproteins (VLDL). These included the identification of microsomal transfer protein, the cotranslational targeting of apoproteinB (apoB) for degradation regulated by the availability of lipids, and the characterization of transport vesicles transporting primordial apoB containing particles to the Golgi. The lipase maturation factor 1, glycosylphosphatidylinositol-anchored high density lipoprotein binding protein 1 and an angiopoietin-like protein play a role in lipoprotein lipase (LPL)-mediated hydrolysis of secreted CMs and VLDL so that the right amount of fatty acid is delivered to the right tissue at the right time. Expression of the low density lipoprotein (LDL) receptor is regulated at both transcriptional and posttranscriptional level. Proprotein convertase subtilisin/ kexin type 9 (PCSK9) has a pivotal role in the degradation of LDL receptor. Plasma remnant lipoproteins bind to specific receptors in the liver, the LDL receptor, VLDL receptor and LDL receptor-like proteins prior to removal from the plasma. Reverse cholesterol transport occurs when lipid free apoAI recruits cholesterol and phospholipid to assemble high density lipoprotein (HDL) particles. The discovery of ABC transporters (ABCA1 and ABCG1) and scavenger receptor class B type I (SR-BI) provided further information on the biogenesis of HDL. In humans HDLcholesterol can be returned to the liver either by direct uptake by SR-BI or through cholesteryl ester transfer protein exchange of cholesteryl ester for triglycerides in apoB lipoproteins, followed by hepatic uptake of apoB containing particles. Cholesterol content in cells is regulated by several transcription factors, including the liver X receptor and sterol regulatory element binding protein. This review summarizes recent advances in knowledge of the molecular mechanisms regulating lipoprotein metabolism.Keywords: ABCA1; angiopoietin-like proteins; apoC; apoAI; apolipoprotein E (apoE); cholesterol ester transfer protein; chylomicron; LDL receptor; lecithin cholesterol acyl transferase; lipoprotein(a); lipoprotein lipase; microsomal transfer protein; propertin convertase subtilisin/ kexin type 9; SR-BI; phospholipid transfer protein; very low density lipoproteins (VLDL). Abstract 1695

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“…7), and macrophages (14). ABCA1 participates in the efflux of excess cholesterol from peripheral cells to HDL (16 -18, 34) and promotes formation of pre-␤-HDL particles by hepatocytes (35) and possibly enterocytes (36). The fall in hepatic cholesterol levels (Fig.…”

Section: Fig 2 Sterol Profiles Of Fplc Fractions From Plasma Of G5g8mentioning

confidence: 99%

Stimulation of Cholesterol Excretion by the Liver X Receptor Agonist Requires ATP-binding Cassette Transporters G5 and G8

York

Bergmann

et al. 2003

Journal of Biological Chemistry

257

193

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Liver X receptor (LXR) is a nuclear receptor that plays a crucial role in orchestrating the trafficking of sterols between tissues. Treatment of mice with a potent and specific LXR agonist, T0901317, is associated with increased biliary cholesterol secretion, decreased fractional cholesterol absorption, and increased fecal neutral sterol excretion. Here we show that expression of two target genes of LXR␣, the ATP-binding cassette (ABC) transporters Abcg5 and Abcg8, is required for both the increase in sterol excretion and the decrease in fractional cholesterol absorption associated with LXR agonist treatment. Mice expressing no ABCG5 and ABCG8 (G5G8 ؊/؊ mice) and their littermate controls were treated for 7 days with T0901317. In wild type animals, treatment with the LXR agonist resulted in a 3-fold increase in biliary cholesterol concentrations, a 25% reduction in fractional cholesterol absorption, and a 4-fold elevation in fecal neutral sterol excretion. In contrast, the LXR agonist did not significantly affect biliary cholesterol levels, fractional cholesterol absorption, or neutral fecal sterol excretion in the G5G8 ؊/؊ mice. Thus Abcg5 and Abcg8 are required for LXR agonist-associated changes in dietary and biliary sterol trafficking. These results establish a central role for ABCG5 and ABCG8 in promoting cholesterol excretion in vivo.Cholesterol is an important structural component of animal cell membranes. The cholesterol required to maintain membrane integrity can be synthesized de novo from acetyl-CoA or can be obtained from cholesterol-containing foods in the diet. The typical Western diet includes ϳ400 mg of cholesterol per day, of which 40 -50% is absorbed in the proximal small intestine. The major pathway by which cholesterol is eliminated from the body is by excretion into bile either as free cholesterol or after conversion to bile acids.A variety of noncholesterol sterols are also present in the diet. The most plentiful of these are the two plant sterols, sitosterol and campesterol. The levels of these sterols in tissues are very low, because plant sterols are poorly absorbed from the intestine and are preferentially secreted into the bile by hepatocytes (1-3).One mechanism by which excess cholesterol and other sterols are eliminated from the body involves the action of two ATP-binding cassette (ABC) 1 half-transporters, ABCG5 and ABCG8 (4, 5). Mutations in either of these genes cause sitosterolemia, a rare autosomal recessive disorder of sterol trafficking (4, 5). Subjects with sitosterolemia have increased fractional absorption of dietary noncholesterol sterols and decreased biliary secretion of plant-and animal-derived sterols (6, 7). Consequently, these patients accumulate sitosterol, as well as other plant-and shellfish-derived neutral sterols, in the blood and tissues (8, 9). Subjects with sitosterolemia also are frequently hypercholesterolemic and develop tendon xanthomas and premature coronary artery disease (8, 10).The pivotal role of ABCG5 and ABCG8 in enterohepatic sterol transport has ...

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ABCA1 Is Essential for Efficient Basolateral Cholesterol Efflux during the Absorption of Dietary Cholesterol in Chickens

Cited by 111 publications

References 72 publications

Loss of Stearoyl-CoA Desaturase-1 Improves Insulin Sensitivity in Lean Mice but Worsens Diabetes in Leptin-Deficient Obese Mice

Loss of Stearoyl-CoA Desaturase-1 Improves Insulin Sensitivity in Lean Mice but Worsens Diabetes in Leptin-Deficient Obese Mice

Recent advances in physiological lipoprotein metabolism

Stimulation of Cholesterol Excretion by the Liver X Receptor Agonist Requires ATP-binding Cassette Transporters G5 and G8

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