Apolipoprotein A-I is required for cholesteryl ester accumulation in steroidogenic cells and for normal adrenal steroid production.

Plump, Andrew S.; Erickson, Sandra K.; Weng, Wei; Partin, John C.; Breslow, Jan L.; Williams, David L.

doi:10.1172/jci118716

Cited by 170 publications

(153 citation statements)

References 59 publications

(35 reference statements)

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“…30 Patients with obesity, insulin resistance, and diabetes have reduced endothelial function even without clinical evidence of cardiovascular disease. 31,32,33 Although endothelial function measurement has not been used as a routine clinical screening tool, clinical studies have demonstrated that endothelial dysfunction is an independent predictor of future cardiovascular events. 34,35 Therapeutic agents such as metformin and PPAR␥ agonists partially restore endothelial function in patients with diabetes.…”

Section: What Processes Cause Diabetic Toxicity?mentioning

confidence: 99%

Diabetic Vascular Disease

Goldberg

Dansky

2006

ATVB

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Abstract-It is well known that humans with diabetes have more atherosclerosis and its complications. The causes of this relationship are, however, unclear. Although recent data show that improved glycemic control reduces arterial disease in type 1 diabetes, other studies have shown that subjects with "prediabetes" have more cardiovascular disease before the development of hyperglycemia. Thus, either hyperglycemia and/or lack of insulin actions are toxic to arteries, or metabolic derangements exclusive of hyperglycemia are atherogenic. For Ͼ50 years animal models of diabetes and atherosclerosis have been used to uncover potential mechanisms underlying diabetes associated cardiovascular disease. Surprisingly, diabetes alone increases vascular disease in only a few select animal models. Increased atherosclerosis has been found in several animals and lines of genetically modified mice; however, diabetes often also leads to greater hyperlipidemia. This makes it difficult to separate the toxic effects of insulin lack and/or hyperglycemia from those caused by the lipids. These studies are reviewed, as well as more recent investigations using new methods to create diabetic-atherosclerotic models.

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Section: What Processes Cause Diabetic Toxicity?mentioning

confidence: 99%

Diabetic Vascular Disease

Goldberg

Dansky

2006

ATVB

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“…4 -6). In addition to its role as a structural element of HDL, apoA-I stimulates cholesterol efflux, is the most potent activator of LCAT (7) and may be important for HDL interactions with scavenger receptor class B type 1 (8,9) and ABCA1 (10,11). * This work was supported in part by a group grant from the Canadian Institutes of Health Research.…”

Section: High Density Lipoproteins (Hdl)mentioning

confidence: 99%

The N-terminal Globular Domain and the First Class A Amphipathic Helix of Apolipoprotein A-I Are Important for Lecithin:Cholesterol Acyltransferase Activation and the Maturation of High Density Lipoprotein in Vivo

Scott¹,

McManus²,

Franklin³

et al. 2001

Journal of Biological Chemistry

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To investigate the role of the N terminus of apolipoprotein A-I (apoA-I) in the maturation of high density lipoproteins (HDL), two N-terminal mutants with deletions of residues 1-43 and 1-65 (referred to as ⌬1-43 and ⌬1-65 apoA-I) were studied. In vitro, these deletions had little effect on cellular cholesterol efflux from macrophages but LCAT activation was reduced by 50 and 70% for the ⌬1-43 and ⌬1-65 apoA-I mutants, respectively, relative to wild-type (Wt) apoA-I. To further define the role of the N terminus of apoA-I in HDL maturation, we constructed recombinant adenoviruses containing Wt apoA-I and two similar mutants with deletions of residues 7-43 and 7-65 (referred to as ⌬7-43 and ⌬7-65 apoA-I, respectively). Residues 1-6 were not removed in these mutants to allow proper cleavage of the pro-sequence in vivo. Following injection of these adenoviruses into apoA-I-deficient mice, plasma concentrations of both ⌬7-43 and ⌬7-65 apoA-I were reduced 4-fold relative to Wt apoA-I. The N-terminal deletion mutants, in particular ⌬7-65 apoA-I, were associated with greater proportions of pre␤-HDL and accumulated fewer HDL cholesteryl esters relative to Wt apoA-I. Wt and ⌬7-43 apoA-I formed predominantly ␣-migrating and spherical HDL, whereas ⌬7-65 apoA-I formed only pre␤-HDL of discoidal morphology. This demonstrates that deletion of the first class A amphipathic ␣-helix has a profound additive effect in vivo over the deletion of the globular domain alone (amino acids 1-43) indicating its important role in the production of mature ␣-migrating HDL. In summary, the combined in vitro and in vivo studies demonstrate a role for the N terminus of apoA-I in lecithin:cholesterol acyltransferase activation and the requirement of the first class A amphipathic ␣-helix for the maturation of HDL in vivo. High density lipoproteins (HDL)1 transport cholesterol from peripheral tissues to the liver in a process known as reverse cholesterol transport (1). This pathway is accepted as a primary mechanism by which HDL exert their anti-atherogenic effects. Nascent HDL are secreted by hepatocytes, liberated from chylomicrons during triglyceride lipolysis, and are derived from HDL remodeling by hepatic lipase and cholesteryl ester transfer protein. The importance of phospholipid transfer protein (PLTP) in the lipidation of this nascent HDL pool has recently emerged, because PLTP-deficient mice exhibit defective phospholipid transfer from triglyceride-rich lipoproteins to HDL, reduced HDL levels, and increased HDL catabolism (2). Efflux of cholesterol and phospholipids from cells provide nascent HDL with lipid constituents. This step is important for steady-state concentrations of HDL, because efflux is a ratelimiting step in HDL maturation as heterozygous mutations in the ATP binding cassette transporter A1 (ABCA1) can cause familial HDL deficiency (3). The combined actions of PLTP and ABCA1 generate larger discoidal pre␤ 2 and pre␤ 3 -HDL from the nascent HDL pool, which are converted to spherical ␣-migrating HDL by the actions of lecithin:...

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“…In HDL, apoA-I is the principal physiological activator of lecithin-cholesterol acyltransferase (11)(12)(13). ApoA-I also promotes high affinity binding of HDL and rHDL particles to cells (14 -17), and analysis of apoA-I-deficient mice highlighted the importance of apoA-I for the delivery of HDL cholesterol to steroidogenic tissues via selective lipid uptake (18).…”

mentioning

confidence: 99%

The Effects of Mutations in Helices 4 and 6 of ApoA-I on Scavenger Receptor Class B Type I (SR-BI)-mediated Cholesterol Efflux Suggest That Formation of a Productive Complex between Reconstituted High Density Lipoprotein and SR-BI Is Required for Efficient Lipid Transport

Liu¹,

Krieger²,

Kan³

et al. 2002

Journal of Biological Chemistry

120

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We have studied the effects of mutations in apoA-I on reconstituted high density lipoprotein (HDL) particle (rHDL(apoA-I)) binding to and cholesterol efflux from wild-type (WT) and mutant forms of the HDL receptor SR-BI expressed by ldlA-7 cells. Mutations in helix 4 or helix 6 of the apoA-I reduced efflux by 79 and 51%, respectively, without substantially altering receptor binding (apparent K d values of 1.1-4.4 g of protein/ml). SR-BI with an M158R mutation bound poorly to rHDL with WT and helix 4 mutant apoA-I; the helix 6 mutant restored tight binding to SR-BI(M158R) (K d values of 48, 60, and 7 g of protein/ml, respectively). SR-BI(M158R)-mediated cholesterol efflux rates, normalized for binding, were high for all three rHDLs (71-111% of control). In contrast, absolute (12-19%) and binding-corrected (24 -47%) efflux rates for all three rHDLs mediated by SR-BI with Q402R/Q418R mutations were very low. We propose that formation of a productive complex between apoA-I in rHDL and SR-BI, in which the lipoprotein and the receptor must either be precisely aligned or have the capacity to undergo appropriate conformational changes, is required for efficient SR-BI-mediated cholesterol efflux. Some mutations in apoA-I and/or SR-BI can result in high affinity, but non-productive, binding that does not permit efficient cholesterol efflux.

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Apolipoprotein A-I is required for cholesteryl ester accumulation in steroidogenic cells and for normal adrenal steroid production.

Cited by 170 publications

References 59 publications

Diabetic Vascular Disease

Diabetic Vascular Disease

The N-terminal Globular Domain and the First Class A Amphipathic Helix of Apolipoprotein A-I Are Important for Lecithin:Cholesterol Acyltransferase Activation and the Maturation of High Density Lipoprotein in Vivo

The Effects of Mutations in Helices 4 and 6 of ApoA-I on Scavenger Receptor Class B Type I (SR-BI)-mediated Cholesterol Efflux Suggest That Formation of a Productive Complex between Reconstituted High Density Lipoprotein and SR-BI Is Required for Efficient Lipid Transport

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