SR-BI-mediated HDL cholesteryl ester delivery in the adrenal gland

doi:10.1016/j.mce.2008.09.011

Molecular and Cellular Endocrinology

Volume 300, Issues 1–2, 5 March 2009, Pages 83-88

https://doi.org/10.1016/j.mce.2008.09.011 Get rights and content

Abstract

In adrenocortical cells, scavenger receptor class B, type I (SR-BI) is localized in specialized plasma membrane compartments, called microvillar channels, that retain high density lipoprotein particles (HDL) and are sites for the selective uptake of cholesteryl esters (CE). Formation of microvillar channels is regulated by adrenocorticotropic hormone (ACTH) and requires SR-BI expression. Subsequent to SR-BI-mediated delivery to the plasma membrane, HDL–CE is metabolized to free cholesterol by hormone sensitive lipase and transported to the mitochondria for steroid synthesis via START domain proteins. The relevance of SR-BI to adrenal steroidogenesis is evident by the impairment of glucocorticoid-mediated stress response in the absence of SR-BI-mediated HDL–CE uptake in mice. On the molecular level, SR-BI mediates HDL–CE selective uptake by forming a hydrophobic channel. In addition, SR-BI facilitates bi-directional flux of cholesterol by modifying the phospholipid content of the plasma membrane. SR-BI most likely accomplishes these functions by forming homo-oligomers in the plasma membrane. Examination of SR-BI oligomerization using fluorescence resonance energy transfer spectroscopy revealed that SR-BI multimerizes via its C-terminal region. Overall, SR-BI is the cell surface receptor responsible for selective uptake of lipoprotein cholesterol and its ultimate delivery to sites of hormone synthesis in steroidogenic tissues.

Section snippets

SR-BI, an atheroprotective HDL receptor

Scavenger receptor class B, type I (SR-BI) is a cell surface glycoprotein that was first identified by its homology to the scavenger receptor CD36 (Calvo and Vega, 1993) and subsequently proven to be a very efficient receptor for cholesterol and cholesteryl ester (CE) transport to and from high density lipoprotein particles (HDL) (Acton et al., 1996, Rigotti et al., 1997) (for review see Connelly and Williams, 2004a, Rhainds and Brissette, 2004, Trigatti et al., 2003). SR-BI has the ability to

SR-BI, a multi-functional protein

Besides binding and mediating the various functions of HDL particles, SR-BI has been shown to be a rather promiscuous receptor that binds ligands such as low density lipoproteins (LDL), very low density lipoprotein (VLDL) remnants, oxidized and acetylated LDL, apoptotic cells, anionic phospholipids and lipopolysaccharide to name a few. Although the role of SR-BI in HDL metabolism has been clearly defined, its role in the metabolic fate of cholesterol from LDL, or other apoB-containing

SR-BI’s role in the adrenal gland

Although SR-BI is expressed in many mammalian tissues and cell types, it is expressed most highly in tissues that are dependent on HDL cholesterol for bile acid or hormone synthesis: liver, ovary, testes and adrenal gland (Acton et al., 1996). Consistent with its expression pattern, alterations in murine SR-BI expression have profound effects on biliary cholesterol excretion, female infertility and adrenal gland cholesteryl ester accumulation (Connelly and Williams, 2004a, Rhainds and

SR-BI-mediated uptake of HDL lipids

SR-BI-mediated selective uptake of HDL–CE is a two-step process: the first step involves lipoprotein binding to the extracellular domain of SR-BI and the second step is the selective transfer of lipid to the plasma membrane. The detailed mechanisms by which SR-BI mediates cholesterol movement between HDL and cells are poorly understood. Reaven et al., 1989, Reaven et al., 1998 found that SR-BI exists in an elaborate cell surface compartment of HDL-filled microvillar channels that are formed by

Future investigation of SR-BI function

Although a great deal is known about the function of SR-BI in HDL cholesterol transport to the adrenal gland, questions still remain. One burning question is whether or not SR-BI-mediated delivery of cholesterol to the adrenal gland is as important in humans as it appears to be in rodents. Early studies in human cells in culture suggested that the LDL receptor was more important for cholesterol delivery. However, the jury is still out since little attention has been paid to the function of

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In the liver, HDL cholesterol uptake facilitates reverse cholesterol transport by delivering surplus peripheral cholesterol to hepatocytes for secretion into bile or for conversion into bile acids. In steroidogenic organs, HDL-derived cholesterol accumulates in the form of cholesterol ester, and these stores are used for the synthesis of steroid hormones (Connelly, 2009; Hoekstra, 2017). The selective HDL cholesterol uptake pathway is distinct from the LDLR pathway, by which LDL particles are taken up and delivered to lysosomes for degradation (Goldstein and Brown, 2015).
The mechanisms underlying sterol transport in mammalian cells are poorly understood. In particular, how cholesterol internalized from HDL is made available to the cell for storage or modification is unknown. Here, we describe three ER-resident proteins (Aster-A, -B, -C) that bind cholesterol and facilitate its removal from the plasma membrane. The crystal structure of the central domain of Aster-A broadly resembles the sterol-binding fold of mammalian StARD proteins, but sequence differences in the Aster pocket result in a distinct mode of ligand binding. The Aster N-terminal GRAM domain binds phosphatidylserine and mediates Aster recruitment to plasma membrane-ER contact sites in response to cholesterol accumulation in the plasma membrane. Mice lacking Aster-B are deficient in adrenal cholesterol ester storage and steroidogenesis because of an inability to transport cholesterol from SR-BI to the ER. These findings identify a nonvesicular pathway for plasma membrane to ER sterol trafficking in mammals.
Cholesterol delivery to the adrenal glands estimated by adrenal venous sampling: An in vivo model to determine the contribution of circulating lipoproteins to steroidogenesis in humans
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Citation Excerpt :
Studies in mice have indicated that scavenger receptor class B, type I (SRBI) plays a pivotal role in the selective uptake of cholesteryl esters from high-density lipoproteins (HDL) particles, which are subsequently stored intracellular and converted into free cholesterol.7,8 Accordingly, SRBI deficiency in rodents results in impaired adrenal steroidogenesis.9–11 Mildly impaired adrenal function has also been documented in human subjects with heterozygous SRBI deficiency.12
Cholesterol, required for adrenal steroid hormone synthesis, is at least in part derived from circulating lipoproteins. The contribution of high-density lipoproteins (HDL) and low-density lipoproteins (LDL) to adrenal steroidogenesis in humans is unclear.
The aim of the study was to determine the extent to which HDL and LDL are taken up by the adrenal glands using samples obtained during adrenal venous sampling (AVS).
AVS was successfully performed in 23 patients with primary aldosteronism. Samples were drawn from both adrenal veins and inferior vena cava (IVC). HDL cholesterol (HDL-C) and lipoprotein particle profiles were determined by nuclear magnetic resonance spectroscopy. Apolipoprotein (apo) A-I and apoB were assayed by immunoturbidimetry.
Plasma HDL-C and HDL and LDL particle concentrations (HDL-P and LDL-P) were not lower in samples obtained from the adrenal veins compared with the IVC (HDL-C, P = .59; HDL-P, P = .06; LDL-P, P = .93). ApoB was lower in adrenal venous plasma than in IVC (P = .026; P < .05 for right adrenal vein). In 13 patients with an aldosterone producing adenoma (APA), apoB was also lower (P = .045) and LDL-P tended to be lower (P = .065) in the APA adrenal vein compared with the IVC. ApoA-I was not lower in adrenal venous plasma compared with the IVC, neither in the whole group (P = .20) nor in the APA subgroup (P = .075).
These in vivo observations suggest that circulating LDL may contribute to adrenal steroidogenesis in humans as inferred from adrenal venous-IVC apoB concentration differences. AVS is a feasible method to investigate the relationships between lipoproteins and steroidogenesis.
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Cholesterol trafficked within plasma lipoproteins is considered to represent an important source of cholesterol that is used for steroidogenesis by the adrenal glands.5–7 Accordingly, studies in rodents have delineated that impaired adrenal steroidogenesis is a feature of scavenger receptor class B, type 1 deficiency, the receptor that plays a pivotal role in cellular uptake of high-density lipoprotein (HDL)-cholesteryl esters.8–10 Likewise, attenuated adrenal function has been documented in a few human subjects with heterozygous scavenger receptor class B, type 1 deficiency.11
Cholesterol trafficked within plasma lipoproteins, in particular high-density lipoproteins (HDL), may represent an important source of cholesterol that is required for adrenal steroidogenesis. Based on a urinary gas chromatography method, compromised adrenal function has been suggested in men but not in women with (genetically determined) low plasma HDL-cholesterol (HDL-C).
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TGP was not decreased but tended to be increased in subjects with low HDL-C (NCEP-ATPIII criteria; P = .094). In univariate analysis, TPG was correlated inversely with HDL-C (r = −0.353, P < .001) and apoA-I (r = −0.263, P = .01). Multivariable linear regression analysis demonstrated that TGP was still inversely related to HDL-C (β = −0.145, P = .019) or alternatively to low HDL-C (β = −0.129, P = .013) taking age, sex, current smoking, and other metabolic syndrome components into account.
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HDLs appear to affect regulatory T cell (Treg) homeostasis, as suggested by the increased Treg counts in HDL-treated mice and by the positive correlation between Treg frequency and HDL-cholesterol levels in statin-treated healthy adults. However, the underlying mechanisms remain unclear. Herein, we show that HDLs, not LDLs, significantly decreased the apoptosis of human Tregs in vitro, whereas they did not alter naïve or memory CD4⁺ T cell survival. Similarly, oleic acid bound to serum albumin increased Treg survival. Tregs bound and internalized high amounts of HDL compared with other subsets, which might arise from the higher expression of the scavenger receptor class B type I by Tregs; accordingly, blocking this receptor hindered HDL-mediated Treg survival. Mechanistically, we showed that HDL increased Treg ATP concentration and mitochondrial activity, enhancing basal respiration, maximal respiration, and spare respiratory capacity. Blockade of FA oxidation by etoxomir abolished the HDL-mediated enhanced survival and mitochondrial activity. Our findings thus suggest that Tregs can specifically internalize HDLs from their microenvironment and use them as an energy source. Furthermore, a novel implication of our data is that enhanced Treg survival may contribute to HDLs' anti-inflammatory properties.

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ReviewSR-BI-mediated HDL cholesteryl ester delivery in the adrenal gland

Abstract

Section snippets

SR-BI, an atheroprotective HDL receptor

SR-BI, a multi-functional protein

SR-BI’s role in the adrenal gland

SR-BI-mediated uptake of HDL lipids

Future investigation of SR-BI function

Journal of Biological Chemistry

Journal of Lipid Research

Molecular & Cellular Endocrinology

Journal of Biological Chemistry

Journal of Biological Chemistry

Journal of Lipid Research

Trends in Endocrinology & Metabolism

Journal of Lipid Research

Journal of Biological Chemistry

Biochemical & Biophysical Research Communications

Journal of Biological Chemistry

Journal of Lipid Research

Journal of Lipid Research

Journal of Lipid Research

Journal of Biological Chemistry

Journal of Biological Chemistry

Journal of Biological Chemistry

Molecular & Cellular Endocrinology

Journal of Biological Chemistry

Journal of Biological Chemistry

Chemistry & Physics of Lipids

Biochimica et Biophysica Acta

Trends in Cardiovascular Medicine

Trends in Cardiovascular Medicine

Trends in Cardiovascular Medicine

Journal of Biological Chemistry

Journal of Lipid Research

Journal of Biological Chemistry

Journal of Biological Chemistry

Journal of Lipid Research

Biochimica et Biophysica Acta

Journal of Lipid Research

International Journal of Biochemistry & Cell Biology

Journal of Biological Chemistry

Journal of Lipid Research

The Journal of Biological Chemistry

Biochimica et Biophysica Acta

Biochimica et Biophysica Acta

Biochimica Biophysics Acta Lipids Lipid Metabolism

Journal of Biological Chemistry

Molecular & Cellular Endocrinology

Journal of Biological Chemistry

Journal of Biological Chemistry

Journal of Biological Chemistry

Journal of Lipid Research

Journal of Biological Chemistry

Journal of Biological Chemistry

Journal of Lipid Research

Journal of Lipid Research

Journal of Lipid Research

Review
SR-BI-mediated HDL cholesteryl ester delivery in the adrenal gland