Endogenous Androgen Deficiency Enhances Diet-Induced Hypercholesterolemia and Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

Hatch, Nicholas; Srodulski, Sarah; Chan, Huei Wei; Zhang, Xuan; Tannock, Lisa R.; King, Victoria

doi:10.1016/j.genm.2012.08.003

Cited by 25 publications

(28 citation statements)

References 38 publications

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“…Female Cyp7a1 knockout mice have a threefold increase in hepatic cholesterol and increased cholesterol absorption while males have minimal increases in cholesterol absorption and hepatic cholesterol (12). Higher cholesterol was found in female compared to male LDL-receptor knockout mice fed a low-fat chow (17). Furthermore, orchidectomy increased cholesterol in males but ovariectomy did not alter 3.6 ± 0.6* 6.8 ± 1.8* † Hepatic triglycerides (nmol/100 mg liver weight) 16 ± 6 22 ± 6 20 ± 7 17 ± 12 23 ± 5 27 ± 3* Serum for lipid panels was allowed to clot at room temperature for 30 min prior to separation and analysis at ARUP laboratories.…”

Section: Articlesmentioning

confidence: 94%

“…cholesterol in females (17). Androgen levels may be protective for hypercholesterolemia, and dietary fat and cholesterol may interplay with sex steroids to alter cholesterol metabolism (17).…”

Section: Articlesmentioning

confidence: 99%

“…Androgen levels may be protective for hypercholesterolemia, and dietary fat and cholesterol may interplay with sex steroids to alter cholesterol metabolism (17). The specific etiology of the IUGR insult differentially impacts the formation of hypercholesterolemia.…”

Section: Articlesmentioning

confidence: 99%

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Combination of intrauterine growth restriction and a high-fat diet impairs cholesterol elimination in rats

et al. 2014

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Background: Intrauterine growth restriction (IUGR) increases the risk of adult-onset hypercholesterolemia. High-fat diet (HFD) consumption potentiates IUGR-induced increased cholesterol. Cholesterol is converted to bile acids by Cyp7a1 in preparation for excretion. We hypothesized that IUGR rats fed a HFD will have increased cholesterol, decreased Cyp7a1 protein levels, and decreased bile acids compared to control rats fed a HFD. Methods: At day 21, IUGR and control pups were placed on one of three diets: a regular chow or one of two HFDs containing 1% or 2% cholesterol. Cholesterol levels and hepatic Cyp7a1 protein levels were quantified a postnatal week 28. results: Both HFDs increased serum cholesterol levels in control rats, and HFD fed IUGR rats had further increased serum cholesterol up to 35-fold. Both HFDs increased hepatic cholesterol levels, and IUGR further increased hepatic cholesterol levels up to fivefold. IUGR decreased hepatic Cyp7a1 protein up to 75%, and hepatic bile acids up to 54%. conclusion: IUGR increased cholesterol and bile acids and decreased Cyp7a1 protein in rats fed a HFD without changing food intake. These findings suggest that IUGR increases the vulnerability of HFD fed rats to hypercholesterolemia via decreased cholesterol conversion to bile acids. i ntrauterine growth restriction (IUGR) predisposes to adultonset hypercholesterolemia (1,2). Epidemiologic studies demonstrate that late-gestation exposure to famine makes individuals more susceptible to hypercholesterolemia only when combined with postnatal consumption of a high-fat diet (HFD) (3). These results suggest that the postnatal nutritional environment impacts cholesterol metabolism differently in IUGR individuals compared their normally grown peers. A better understanding of the mechanism through which IUGR combined with a postnatal HFD impacts cholesterol metabolism would provide a foundation to pursue further research into preventing hypercholesterolemia in IUGR individuals.While the effects of HFD consumption in individuals born IUGR are not well understood, the detrimental effects of HFD consumption in the general population has been extensively documented. HFD consumption often leads to hypercholesterolemia and eventually cardiovascular disease (4). Higher cholesterol levels increase the risk of cardiovascular disease in a continuous, graded fashion (5,6). IUGR may potentiate hypercholesterolemia in individuals that consume a HFD and thus increase morbidity and mortality in this population. The impact of IUGR on cholesterol levels in humans is more evident in the recent decades due to the changing Western diet (7). Average daily fat and cholesterol intake in the United States is ~23-33 g of saturated fat and up to 400 mg cholesterol, both well above the recommended daily intake of ~16 g or no more than 7% of caloric intake for saturated fat and 200 mg cholesterol (7).The liver is the primary organ for regulating both serum and hepatic cholesterol levels. Cholesterol homeostasis is regulated by a series of hepatic genes...

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Section: Articlesmentioning

confidence: 94%

Section: Articlesmentioning

confidence: 99%

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Combination of intrauterine growth restriction and a high-fat diet impairs cholesterol elimination in rats

et al. 2014

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“…Castrated animals showed a further elevation in VLDL that combined with their reduced HDL levels ( Fig. 2A, C ) may provide a mechanistic interpretation of the results of a recent study showing that castrated Ldlr Ϫ / Ϫ mice fed a low-fat diet develop more severe atherosclerotic lesions than sham-operated animals ( 50 ). At fi rst glance, it may appear that the reduction in plasma HDL levels is insignifi cant because sham-operated mice already have reduced HDL levels compared with control C57BL/6 mice.…”

Section: Discussionmentioning

confidence: 59%

The low density lipoprotein receptor modulates the effects of hypogonadism on diet-induced obesity and related metabolic perturbations

Constantinou

Mpatsoulis

Natsos

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.orgTestosterone , a steroid hormone with an important role in male sexual differentiation, maintenance of libido, and erectile function ( 1, 2 ), is also a central modulator of key metabolic processes associated with metabolic syndrome. In humans, testosterone defi ciency (TD) alters carbohydrate, lipid, and protein metabolism, thus contributing to oxidative stress, endothelial dysfunction, and increased production of proinfl ammatory factors ( 3 ). TD is considered as a primary risk factor for a number of disorders including obesity, metabolic syndrome, dyslipidemia, endothelial cell dysfunction, vascular disease, insulin resistance, and type 2 diabetes mellitus ( 4-8 ). Likewise, data from the Massachusetts Male Aging Study suggest that obesity leads to decreased levels of total and free testosterone, with follow-up levels lowest among men who remained or became obese ( 9 ).Additional insights into the role of androgens in maintaining human health have been obtained following androgen deprivation therapy (ADT), which is often used in the treatment of prostate cancer (PCa). Metabolic complications of ADT, such as metabolic syndrome, insulin resistance, and type 2 diabetes mellitus have highlighted key avenues of human pathology associated with this treatment ( 10 ). ADT in men with PCa resulted in increased total cholesterol, LDL cholesterol (LDL-C), and TG levels ( 11, 12 ). Abbreviations: ADT , androgen deprivation therapy; AUC, area under the curve; BAT, brown adipose tissue; Cox4, cytochrome c oxidase subunit 4; EE, energy expenditure; GTT, glucose tolerance test; hCetp, human cholesteryl ester transfer protein; HDL-C, HDL cholesterol; LBM, lean body mass; Ldlr, LDL receptor; Lrp1, LDL receptor-related protein 1; PCa, prostate cancer; RER, respiratory exchange ratio; TD, testosterone defi ciency; Ucp1, uncoupling protein 1; VCO 2 , carbon dioxide production expressed as the difference of carbon dioxide exiting from carbon dioxide entering the metabolic cage; VO 2 , oxygen consumption expressed as the difference between oxygen entering and oxygen exiting the metabolic cage; WAT, white adipose tissue.

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“…Clinical studies reported that testosterone levels inversely correlated with total cholesterol and LDL cholesterol levels [11][12][13] . In addition, animal studies demonstrated highly elevated cholesterol levels in testosterone-deficient male mice 14,15 . These findings suggested that testosterone serves a valuable role in regulating serum lipids.…”

Section: Introductionmentioning

confidence: 99%

Effects of Testosterone Replacement on Insulin Sensitivity, Blood Glucose, Serum Lipids and Vitamin D Concentration in a Rat Model of Andropause

Rezk¹

2017

IJCEMS

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Abstract:Background: Testosterone facilitates various metabolic processes in the bones, muscles, bone marrow, brain and immune system. Testosterone deficiency may contribute to cardiovascular diseases, central obesity and metabolic dysfunction. Aim: to investigate the effects of testosterone deficiency on blood glucose levels, insulin sensitivity, vitamin D, Homeostatic model assessment of insulin resistance (HOMA-IR), Homeostatic model assessment for beta function (HOMA-IR) and serum lipids in rat models of andropause. Methods, 48 male rats divided into 4 equal groups (n=12/group); a) Control (C) group. b) Orchiectomy (O) group underwent bilateral removal of the testicles. c) Orchiectomy and treated (O+T) group given daily IM testosterone replacement therapy for 7 days, d) Sham and treated (Sh+T) group in which sham operated rats were given the same daily dose of T as O+T group for 7 days. Results: we found that plasma glucose concentration increased significantly (P<0.001) in O group. This increase was corrected by testosterone injection in O+T group. In (Sh+T) group, there is a significant reduction in serum glucose (P<0.001). We also found that insulin level reduced significantly (P<0.001) in O group. This reduction in insulin level was corrected by testosterone. In (Sh+T) group, insulin level increased significantly. 25-OHVD3 was reduced significantly (P<0.05) in O group and increased significantly in O+T group. HOMA-IR level decreased significantly (P<0.001) and this reduction was corrected by Testosterone. HOMA-β reduced significantly (P<0.001) and this reduction was corrected by Testosterone in O+T group. In SH group, there is a marked increase in HOMA-β. We also found insignificant differences between the four groups in serum triglycerides. However, we found very highly significant differences in total cholesterol, LDL and VLDL between C group and O group and very highly significant differences between O+T group and Sh+T group in comparison with O group. We also found significant differences in serum HDL-c in (O) group in comparison with (C) group and between O+T and Sh+T groups in comparison with O group. In conclusion, we found significant reduction in 25-OH(VD), Testosterone, Insulin, HOMA-IR and HOMA-B and significant increase in glucose serum levels in O group and these changes were corrected by Testosterone injection in O+T group. We also found insignificant differences between the four groups in serum triglycerides. However, we found highly significant differences in total cholesterol, LDL, HDL-c and VLDL between C group and O group and very highly significant differences between O+T group and Sh+T group in comparison with O group.

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Endogenous Androgen Deficiency Enhances Diet-Induced Hypercholesterolemia and Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

Cited by 25 publications

References 38 publications

Combination of intrauterine growth restriction and a high-fat diet impairs cholesterol elimination in rats

Combination of intrauterine growth restriction and a high-fat diet impairs cholesterol elimination in rats

The low density lipoprotein receptor modulates the effects of hypogonadism on diet-induced obesity and related metabolic perturbations

Effects of Testosterone Replacement on Insulin Sensitivity, Blood Glucose, Serum Lipids and Vitamin D Concentration in a Rat Model of Andropause

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