Simvastatin treatment aggravates the glucocorticoid insufficiency associated with hypocholesterolemia in mice

Ouweneel, Amber B.; Sluis, Ronald J. van der; Nahon, Joya E.; Eck, Miranda Van; Hoekstra, Menno

doi:10.1016/j.atherosclerosis.2017.02.014

Cited by 11 publications

(9 citation statements)

References 32 publications

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“…The administration of simvastatin (20 mg/kg/day) via the oral route (mixed with the HFD) had no significant effect on blood lipid profile or body weight in mice. In accordance with our results, previous studies also reported non-significant effects of simvastatin on blood lipid profile and body weight in mice [ 51 , 52 ]. Even a dosage as high as 100 mg/kg of simvastatin had no significant effect on mice blood lipid profile, which could be due to a strong compensatory increase in HMG-CoA reductase that occurs in this species [ 53 ].…”

Section: Discussionsupporting

confidence: 93%

Abelmoschus Esculentus (L.) Moench’s Peel Powder Improves High-Fat-Diet-Induced Cognitive Impairment in C57BL/6J Mice

Prom-in

Kaewsrichan

Wangpradit

et al. 2020

IJERPH

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Okra peel exhibits numerous therapeutic effects. This study explores the potential ameliorative effects of okra peel powder on high-fat-diet (HFD)-induced hypercholesterolemia and cognitive deficits. Thirty-six C57BL/6J male mice were randomly divided into six groups (n = 6 per group): (i) control, mice fed with a normal diet; (ii) HFD, mice fed with HFD; (iii) HFD-SIM, mice fed with HFD and given simvastatin (20 mg/kg/day); (iv) HFD-OP1; (v) HFD-OP2; (vi) HFD-OP3, mice fed with HFD and okra peel (200, 400, or 800 mg/kg/day, respectively). Following 10 weeks of treatments, the mice were subjected to the Morris water maze (MWM). Parameters such as weekly average body weight, food intake, and blood lipid profiles were also recorded. The HFD group showed a profound increase in total cholesterol and low-density lipoprotein concentration compared to the control group. All okra-treated and HFD-SIM groups performed better than the HFD group during acquisition trials, whereas only the HFD-OP1 produced a significantly higher number of entries into the platform zone during the probe trial. In sum, all three okra doses improved the learning ability of the mice. However, only the lowest dose of okra significantly improved the spatial reference memory retention.

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Section: Discussionsupporting

confidence: 93%

Abelmoschus Esculentus (L.) Moench’s Peel Powder Improves High-Fat-Diet-Induced Cognitive Impairment in C57BL/6J Mice

Prom-in

Kaewsrichan

Wangpradit

et al. 2020

IJERPH

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“…As cholesterol is a precursor of glucocorticoid synthesis, AI may be present when serum cholesterol is lower than normal. An animal study demonstrated that in mice treated with high-dose simvastatin for 3 days, AI could be aggravated by their hypocholesterolemic condition [28]. Our results appear to support that hypothesis.…”

Section: Discussionsupporting

confidence: 84%

Predictive Factors of Adrenal Insufficiency in Outpatients with Indeterminate Serum Cortisol Levels: A Retrospective Study

et al. 2020

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Background and Objectives: To diagnose adrenal insufficiency (AI), adrenocorticotropic hormone (ACTH) stimulation tests may need to be performed, but those tests may not be available in some institutions. In addition, they may not be necessary for some patients. The objective of this study was to identify clinical and biochemical factors that could facilitate AI diagnosis in outpatient departments and decrease the number of unnecessary dynamic tests. Materials and Methods: This seven-year retrospective study was performed in a tertiary care medical center. A total of 517 patients who had undergone ACTH stimulation tests in the outpatient department were identified. AI was described as a peak serum cortisol level of <18 µg/dL at 30 or 60 min after stimulation. The associations between clinical factors, biochemical factors, and AI were analyzed using the Poisson regression model and reported by the risk ratio (RR). Results: AI was identified in 128 patients (24.7%). Significant predictive factors for the diagnosis of AI were chronic kidney disease (RR = 2.52, p < 0.001), Cushingoid appearance (RR = 3.44, p < 0.001), nausea and/or vomiting (RR = 1.84, p = 0.003), fatigue (RR = 1.23, p < 0.001), serum basal cortisol <9 µg/dL (RR = 3.36, p < 0.001), serum cholesterol <150 mg/dL (RR = 1.26, p < 0.001), and serum sodium <135 mEq/L (RR = 1.09, p = 0.001). The predictive ability of the model was 83% based on the area under the curve. Conclusion: The easy-to-obtain clinical and biochemical factors identified may facilitate AI diagnosis and help identify patients with suspected AI. Using these factors in clinical practice may also reduce the number of nonessential dynamic tests for AI.

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“…Knockout of apolipoprotein A-I (apoA-I), the main structural lipoprotein on HDL, reduced plasma HDL-C levels by ~74% and essentially depleted lipid droplets in the adrenal cortex. The production of corticosteroids under a basal or stress condition was also significantly reduced in apoA-I knockout mice ( 34 – 36 ). Like apoA-I knockout mice, Surf4 LKO mice display a similar reduction in plasma HDL cholesterol levels under fasting and non-fasting conditions.…”

Section: Discussionmentioning

confidence: 98%

Loss of Hepatic Surf4 Depletes Lipid Droplets in the Adrenal Cortex but Does Not Impair Adrenal Hormone Production

Chang

Zhao

Qin

et al. 2021

Front. Cardiovasc. Med.

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The adrenal gland produces steroid hormones to play essential roles in regulating various physiological processes. Our previous studies showed that knockout of hepatic Surf4 (Surf4LKO) markedly reduced fasting plasma total cholesterol levels in adult mice, including low-density lipoprotein and high-density lipoprotein cholesterol. Here, we found that plasma cholesterol levels were also dramatically reduced in 4-week-old young mice and non-fasted adult mice. Circulating lipoprotein cholesterol is an important source of the substrate for the production of adrenal steroid hormones. Therefore, we investigated whether adrenal steroid hormone production was affected in Surf4LKO mice. We observed that lacking hepatic Surf4 essentially eliminated lipid droplets and significantly reduced cholesterol levels in the adrenal gland; however, plasma levels of aldosterone and corticosterone were comparable in Surf4LKO and the control mice under basal and stress conditions. Further analysis revealed that mRNA levels of genes encoding enzymes important for hormone synthesis were not altered, whereas the expression of scavenger receptor class B type I (SR-BI), low-density lipoprotein receptor (LDLR) and 3-hydroxy-3-methyl-glutaryl-CoA reductase was significantly increased in the adrenal gland of Surf4LKO mice, indicating increased de novo cholesterol biosynthesis and enhanced LDLR and SR-BI-mediated lipoprotein cholesterol uptake. We also observed that the nuclear form of SREBP2 was increased in the adrenal gland of Surf4LKO mice. Taken together, these findings indicate that the very low levels of circulating lipoprotein cholesterol in Surf4LKO mice cause a significant reduction in adrenal cholesterol levels but do not significantly affect adrenal steroid hormone production. Reduced adrenal cholesterol levels activate SREBP2 and thus increase the expression of genes involved in cholesterol biosynthesis, which increases de novo cholesterol synthesis to compensate for the loss of circulating lipoprotein-derived cholesterol in the adrenal gland of Surf4LKO mice.

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Simvastatin treatment aggravates the glucocorticoid insufficiency associated with hypocholesterolemia in mice

Cited by 11 publications

References 32 publications

Abelmoschus Esculentus (L.) Moench’s Peel Powder Improves High-Fat-Diet-Induced Cognitive Impairment in C57BL/6J Mice

Abelmoschus Esculentus (L.) Moench’s Peel Powder Improves High-Fat-Diet-Induced Cognitive Impairment in C57BL/6J Mice

Predictive Factors of Adrenal Insufficiency in Outpatients with Indeterminate Serum Cortisol Levels: A Retrospective Study

Loss of Hepatic Surf4 Depletes Lipid Droplets in the Adrenal Cortex but Does Not Impair Adrenal Hormone Production

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