Enhanced Lipoprotein Lipase Secretion and Foam Cell Formation by Macrophages of Patients with Growth Hormone Deficiency: Possible Contribution to Increased Risk of Atherogenesis?

Type 2 diabetics have a higher risk for atherosclerosis, but the mechanisms underlying the increased risk are poorly understood. Macrophages, which are activated in type 2 diabetes (T2D) and have a role in all stages of atherogenesis, are an attractive link. Our hypothesis is that T2D promotes macrophage dysfunction to promote atherosclerosis. To investigate the relationship between T2D and macrophage dysfunction, we used a proteomics approach to identify dysregulated proteins secreted from peritoneal macrophages in a diet induced mouse model of obesity and insulin resistance in the absence of hypercholesterolemia. Twenty-seven T2D responsive proteins were identified that predict defects in many of the critical functions of macrophages in atherosclerosis (e.g. decreased apoE- cholesterol efflux; decreased MFGE8 – efferocytosis, increased MMP12- matrix degradation). The macrophages from lean and obese mice were not lipid loaded, but the obese macrophages accumulated significantly more cholesterol when exposed to high levels of atherogenic lipoproteins in vitro suggesting that dysregulation of the T2D responsive proteins in diabetic mice render macrophages more susceptible to cholesterol loading. Importantly, many of these same protein changes, which were present in atherosclerotic Ldlr-/- mice with T2D, were normalized when these mice were fed non-diabetogenic hypercholesterolemic diets. Thus, foam cell formation in the presence and absence of T2D produces distinct effects on macrophage protein levels, and hence function. Further, we identify IFNγ as a mediator of the T2D responsive protein dysfunction. IFNγ, but not other cytokines, insulin or glucose, promote the T2D responsive protein dysregulation and increased susceptibility to cholesterol accumulation in vitro and the dysregulation is not observed in macrophage foam cells obtained from obese, diabetic IFNγ receptor 1 knockout animals. We also demonstrate that IFNγ can target these proteins in arterial wall macrophages in vivo . These studies suggest that IFNγ is an important mediator of macrophage dysfunction in T2D that may contribute to the enhanced cardiovascular risk in these patients.

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Macrophage Lipoprotein Lipase Promotes Foam Cell Formation and Atherosclerosis in Low Density Lipoprotein Receptor-deficient Mice

Journal of Biological Chemistry ◽

10.1074/jbc.m002423200 ◽

2000 ◽

Vol 275 (34) ◽

pp. 26293-26299 ◽

Cited By ~ 110

Author(s):

Vladimir R. Babaev ◽

Mayur B. Patel ◽

Clay F. Semenkovich ◽

Sergio Fazio ◽

MacRae F. Linton

Keyword(s):

Lipoprotein Lipase ◽

Foam Cell ◽

Low Density Lipoprotein ◽

Cell Formation ◽

Density Lipoprotein ◽

Foam Cell Formation ◽

Low Density ◽

Lipoprotein Receptor ◽

Density Lipoprotein Receptor ◽

Deficient Mice

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Insulin‐like growth factor I (IGF‐1) downregulates lipoprotein lipase and suppresses atherosclerotic foam cell formation in vivo and in vitro

The FASEB Journal ◽

10.1096/fasebj.23.1_supplement.593.1 ◽

2009 ◽

Vol 23 (S1) ◽

Author(s):

Sergiy Sukhanov ◽

Charlotte Vaughn ◽

Yusuke Higashi ◽

Jane Titterington ◽

Patrick Delafontaine

Keyword(s):

Growth Factor ◽

Lipoprotein Lipase ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Insulin Like Growth Factor ◽

Factor I ◽

Growth Factor I

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Skin morphological changes in growth hormone deficiency and acromegaly

Acta Endocrinologica ◽

10.1530/eje.0.1450147 ◽

2001 ◽

pp. 147-153 ◽

Cited By ~ 33

Author(s):

M Lange ◽

J Thulesen ◽

U Feldt-Rasmussen ◽

NE Skakkebaek ◽

N Vahl ◽

...

Keyword(s):

Growth Hormone ◽

Growth Hormone Deficiency ◽

Morphological Changes ◽

Hormone Deficiency ◽

Sweat Glands ◽

Gh Treatment ◽

Sweat Secretion ◽

Increased Risk ◽

Significant Difference ◽

Eccrine Sweat

OBJECTIVE: To evaluate the histomorphology of skin and its appendages, especially eccrine sweat glands, in patients with GH disorders, because reduced sweating ability in patients with growth hormone deficiency (GHD) is associated with increased risk of hyperthermia under stressed conditions. DESIGN AND METHODS: A skin biopsy was obtained from 17 patients with GHD treated with GH, five patients with untreated GHD, 10 patients with active acromegaly and 13 healthy controls. RESULTS: The sweat secretion rate (SSR) was significantly decreased in both the untreated (median 41 mg/30 min, range 9-79 mg/30 min) and the GH-treated (median 98 mg/30 min, range 28-147 mg/30 min) patients with GHD compared with that in controls (median 119 mg/30 min, range 90-189 mg/30 min; P=0.001 and 0.01 respectively). Epidermal thickness was significantly decreased in both untreated (median 39 microm, range 28-55 microm) and GH-treated patients with GHD (median 53 microm, range 37-100 microm), compared with that in controls (median 66 microm, range 40-111 microm; P<0.02). A statistically non-significant tendency towards thinner epidermis (median 59 microm, range 33-83 microm) was recorded in acromegalic patients (P=0.08) compared with controls. There was no significant difference in the area of the sebaceous glands in the biopsies between the three groups and the controls. The area of eccrine sweat gland glomeruli was significantly decreased in the untreated patients with GHD (median 16407 microm2, range 12758-43976 microm2) compared with that in controls (median 29446 microm2, range 13511-128661 microm2; P=0.03), but there was no significant difference between the GH-treated patients with GHD and controls. CONCLUSIONS: We conclude that GH, either directly or via IGF-I, may have both a structural and a functional effect on human skin and its appendages, and that patients with GHD have histomorphological changes in skin compared with controls. Importantly, these changes are not fully reversed despite long-term and adequate GH treatment in patients with childhood onset GHD.

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Correlation of Significantly Decreased Serum Circulating Mesencephalic Astrocyte-Derived Neurotrophic Factor Level With an Increased Risk of Future Cardiovascular Disease in Adult Patients With Growth Hormone Deficiency

Frontiers in Endocrinology ◽

10.3389/fendo.2021.671126 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ziyu Ren ◽

Yunting Wang ◽

Qing Chen ◽

Jiangchuan Long ◽

Rui Zhang ◽

...

Keyword(s):

Insulin Resistance ◽

Cardiovascular Disease ◽

Growth Hormone ◽

Lipid Metabolism ◽

Growth Hormone Deficiency ◽

Neurotrophic Factor ◽

Hormone Deficiency ◽

Control Group ◽

Increased Risk ◽

Normal Controls

ObjectiveAdult growth hormone deficiency (AGHD) is a rare chronic inflammatory disease caused by damage to the pituitary gland and is accompanied by disorders of multiple metabolic pathways. By examining the correlation between the serum mesencephalic astrocyte-derived neurotrophic factor (MANF) levels of AGHD patients and those of normal controls, we hope to elucidate the close relationship among MANF, lipid metabolism and insulin resistance in AGHD and discuss the potential therapeutic value of MANF.MethodsThis study included 101 AGHD patients and 100 healthy subjects matched for sex, age, height, and weight. Anthropometric parameters and biochemical indicators such as body mass index, waist circumference, hip circumference, serum MANF level, blood lipids and insulin level were measured. The above patients were also divided into several subgroups for correlation analysis based on indicators such as insulin resistance and BMI.ResultsThe serum circulating MANF content of AGHD patients was significantly lower than that of the normal control group (5.235 (0.507-17.62) ng/ml (n=101) vs. 10.30 (1.84-16.65) ng/ml (n=100); p<0.0001), and circulating MANF levels were linearly correlated with HOMA-IR in the AGHD population (R=0.481, P=0.0041). When MANF was at pathological concentrations (lower than the mean circulating MANF of normal controls), the lowest concentration tertile (OR=21.429 p<0.0001) had a significantly higher disease odds ratio, Framingham risk score and 10-year risk of atherosclerotic cardiovascular disease than the highest concentration tertile.ConclusionsMANF has a significant correlation with insulin resistance in the AGHD state. There is a strong correlation with abnormal glucose and lipid metabolism in the obese AGHD population. MANF is also a good assessment factor for the risk of cardiovascular disease in AGHD patients and has excellent therapeutic potential.

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Human ATP–Binding Cassette G1 Controls Macrophage Lipoprotein Lipase Bioavailability and Promotes Foam Cell Formation

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.111.243519 ◽

2012 ◽

Vol 32 (9) ◽

pp. 2223-2231 ◽

Cited By ~ 32

Author(s):

Maryline Olivier ◽

Michael W. Tanck ◽

Ruud Out ◽

Elise F. Villard ◽

Bart Lammers ◽

...

Keyword(s):

Lipoprotein Lipase ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Atp Binding ◽

Atp Binding Cassette

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An Innate Immunity Signaling Process Suppresses Macrophage ABCA1 Expression through IRAK-1-Mediated Downregulation of Retinoic Acid Receptor α and NFATc2

Molecular and Cellular Biology ◽

10.1128/mcb.00541-09 ◽

2009 ◽

Vol 29 (22) ◽

pp. 5989-5997 ◽

Cited By ~ 37

Author(s):

Urmila Maitra ◽

John S. Parks ◽

Liwu Li

Keyword(s):

Innate Immunity ◽

Retinoic Acid ◽

Cholesterol Efflux ◽

Foam Cell ◽

Cell Formation ◽

Proximal Promoter ◽

Foam Cell Formation ◽

Wild Type ◽

Increased Risk ◽

Abca1 Expression

ABSTRACT ATP-binding cassette transporter A1 (ABCA1) plays a central role in promoting cholesterol efflux from macrophages, thereby reducing the risk of foam cell formation and atherosclerosis. The expression of ABCA1 is induced by members of the nuclear receptor family of transcription factors, including retinoic acid receptors (RARs). A key innate immunity signaling kinase, IRAK-1, has been associated with an increased risk of atherosclerosis in humans and mice. This prompted us to investigate the potential connection between IRAK-1 and the expression of ABCA1. Here, we demonstrate that nuclear RARα levels are dramatically elevated in IRAK-1−/− macrophages. Correspondingly, IRAK-1−/− macrophages exhibit increased expression of ABCA1 mRNA and protein, as well as elevated cholesterol efflux in response to the RAR ligand ATRA. Analysis of the ABCA1 proximal promoter revealed binding sites for both RAR and NFAT. Chromatin immunoprecipitation assays demonstrated increased binding of RARα and NFATc2 to the ABCA1 promoter in IRAK-1−/− macrophages compared to wild-type macrophages. Additionally, lipopolysaccharide pretreatment reduced the nuclear levels of RARα and decreased ABCA1 expression and cholesterol efflux in wild-type but not in IRAK-1−/− cells. In summary, this study reveals a novel connection between innate immunity signaling processes and the regulation of ABCA1 expression in macrophages and defines a potential therapeutic target for treating atherosclerosis.

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