1846-P: Low-Dose Dihydrotestosterone Increased Lipogenic Proteins Resulting in Increased NAFLD via Regulation of SREBP1c in Liver Tissue of Normal Weight Female Mice

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1846-P
Author(s):  
STANLEY ANDRISSE
Keyword(s):  
Liver Tissue ◽  
Low Dose ◽  
Normal Weight ◽  
Female Mice

scholarly journals DHT causes liver steatosis via transcriptional regulation of SCAP in normal weight female mice

2021 ◽  
Author(s):  
Tina Seidu ◽  
Patrick McWhorter ◽  
Jessie Myer ◽  
Rabita Alamgir ◽  
Nicole Eregha ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Protein Expression ◽  
Low Dose ◽  
De Novo ◽  
Polycystic Ovary ◽  
Liver Steatosis ◽  
Normal Weight ◽  
De Novo Lipogenesis ◽  
Hepatic Lipid ◽  
Female Mice

Hyperandrogenemia (HA) is a hallmark of polycystic ovary syndrome (PCOS) and is an integral element of nonalcoholic fatty liver disease (NALFD) in females. Administering low dose dihydrotestosterone (DHT) induced a normal weight PCOS-like female mouse model displaying NAFLD. The molecular mechanism of HA-induced NAFLD has not been fully determined. We hypothesized that DHT would regulate hepatic lipid metabolism via increased SREBP1 expression leading to NAFLD. We extracted liver from control and low dose DHT female mice; and performed histological and biochemical lipid pro-files, Western blot, immunoprecipitation, chromatin immunoprecipitation, and real-time quantitative PCR analyses. DHT lowered the 65 kD form of cytosolic SREBP1 in the liver compared to controls. However, DHT did not alter the levels of SREBP2 in the liver. DHT mice displayed increased SCAP protein expression and SCAP-SREBP1 binding compared to controls. DHT mice exhibited increased AR binding to intron-8 of SCAP leading to increased SCAP mRNA compared to controls. FAS mRNA and protein expression was increased in liver of DHT mice compared to controls. p-ACC levels were unaltered in liver. Other lipid metabolism pathways were examined in liver, but no changes were observed. Our findings support evidence that DHT increased de novo lipogenic proteins resulting in increased hepatic lipid content via regulation of SREBP1 in liver. We show that in the presence of DHT the SCAP-SREBP1 interaction was elevated leading to increased nuclear SREBP1 resulting in increased de novo lipogenesis. We propose that the mechanism of action may be increased AR binding to an ARE in SCAP intron-8.

Abstract P295: Endothelial Sodium Channel Activation Promotes Cardiac Stiffness in Obese Female Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Javad Habibi ◽  
Annayya R Aroor ◽  
Lixin Ma ◽  
Guanghong Jia ◽  
Adam Whaley-Connell ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Low Dose ◽  
Interstitial Fibrosis ◽  
Diastolic Heart Failure ◽  
The United States ◽  
High Fat ◽  
Female Mice ◽  
Obese Female ◽  
High Fructose ◽  
Endothelial Stiffness

Cardiac diastolic dysfunction (DD) and diastolic heart failure is increasing in concert with obesity and aging population in the United States. In obese and diabetic women, DD is more common than in their male counterparts. This disproportionate increase in DD in obese females may partly explain their loss of sex-related cardiovascular (CV) disease protection. Recent studies have suggested a role for endothelial sodium channel (ENaC) activation in promotion of endothelial stiffness and suppression of flow- (nitric oxide) mediated vasodilation. Moreover, increased mineralocorticoid receptor (MR) activation mediated endothelial stiffness is promoted, in part, by ENaC activation. In this regard, we have recently reported increased plasma aldosterone levels, aortic and cardiac stiffness, and cardiac and vascular MR expression in female mice fed a high fat and high fructose diet (western diet [WD]). This increase in CV stiffness was prevented by very low dose MR antagonism. Accordingly, we hypothesized that inhibition of MR-mediated ENaC activation by using a very low dose of the ENaC inhibitor, amiloride would prevent cardiac stiffening (DD) in WD-fed female mice. Four week old C57BL6/J mice were fed a WD containing high fat (46%), sucrose (17.5%), and high fructose corn syrup (17.5%) with or without a very low dose of amiloride (1mg/kg/day) for 16 weeks. Amiloride significantly attenuated WD-induced impairment of cardiac relaxation in vivo as measured by high resolution magnetic resonance imaging (MRI) as well as cardiac interstitial fibrosis as measured by immunohistochemistry by picrosirius red staining. Moreover, amiloride prevented the development of DD in obese female mice without having effects on blood pressure. These observations support a role for ENaC activation in diet-induced cardiac stiffening (DD) in obese females.

Methylation changes in muscle and liver tissues of male and female mice exposed to acute and chronic low-dose X-ray-irradiation

2004 ◽  
Vol 548 (1-2) ◽  
pp. 75-84 ◽  
Author(s):  
Olga Kovalchuk ◽  
Paula Burke ◽  
Jill Besplug ◽  
Mark Slovack ◽  
Jody Filkowski ◽  
...  
Keyword(s):  
Low Dose ◽  
Male And Female ◽  
X Ray ◽  
Female Mice ◽  
Liver Tissues

scholarly journals DHT Causes Liver Steatosis via Transcriptional Regulation of SCAP in Lean female Mice

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A807-A807
Author(s):  
Stanley Andrisse ◽  
Jessie Myer ◽  
Dilip “Bobby” Bogle ◽  
Nicole Eregha ◽  
Taylor Lofton
Keyword(s):  
Lipid Metabolism ◽  
Protein Expression ◽  
Low Dose ◽  
De Novo ◽  
Polycystic Ovary ◽  
Liver Steatosis ◽  
De Novo Lipogenesis ◽  
Alcoholic Fatty Liver ◽  
Female Mice ◽  
Real Time Quantitative Pcr

Abstract Hyperandrogenemia (HA) and insulin resistance are hallmarks of polycystic ovary syndrome (PCOS). These hallmarks are also integral elements of non-alcoholic fatty liver disease (NALFD). Administering low dose dihydrotestosterone (DHT) induced a lean PCOS-like female mouse model. The molecular mechanism of HA-induced NAFLD has not been determined. We hypothesized that low dose DHT would interrupt hepatic lipid metabolism leading to NAFLD. We extracted white adipose tissue (WAT), liver, and skeletal muscle from control and low dose DHT female mice; and performed histological and biochemical lipid profiles, Western blot, immunoprecipitation, chromatin immunoprecipitation, and real-time quantitative PCR analyses. DHT lowered the 65 kD form of cytosolic SREBP1 in the liver and WAT compared to controls. However, DHT did not alter the levels of the active and inactive forms of SREBP2 in the liver and WAT. DHT increased SCAP protein expression and SCAP-SREBP1 binding via AR binding to intron-8 of SCAP leading to increased SCAP mRNA. FAS mRNA and protein expression was increased in liver of DHT mice. p-ACC levels were unaltered in liver but decreased in WAT. Other lipid metabolism pathways were examined in liver and WAT, but no changes were observed. Our findings suggest that DHT increased de novo lipogenic proteins resulting in increased NAFLD via regulation of SREBP1 in liver. We show that in the presence of DHT the SCAP-SREBP1 interaction is elevated leading to increased nuclear SREBP1 resulting in increased de novo lipogenesis. We propose that the mechanism of action is increased AR binding to an ARE in SCAP intron-8.

scholarly journals Low‐Dose Dihydrotestosterone Lowers Lipogenic Master Regulator in Liver and Adipose Tissue from Female Mice

2019 ◽  
Vol 33 (S1) ◽  
Author(s):  
Stanley Andrisse ◽  
Patrick McWhorter ◽  
Tina Seidu ◽  
Rabita Alamgir
Keyword(s):  
Adipose Tissue ◽  
Low Dose ◽  
Master Regulator ◽  
Female Mice

scholarly journals Prolonged low-dose dioxin exposure impairs metabolic adaptability to high-fat diet feeding in female but not male mice

2020 ◽  
Author(s):  
Geronimo Matteo ◽  
Myriam P Hoyeck ◽  
Hannah L Blair ◽  
Julia Zebarth ◽  
Kayleigh RC Rick ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Plasma Insulin ◽  
Low Dose ◽  
Dependent Manner ◽  
High Fat ◽  
Male And Female ◽  
Female Mice ◽  
Insulin Levels ◽  
Plasma Insulin Levels

AbstractObjectiveHuman studies consistently show an association between exposure to persistent organic pollutants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka “dioxin”), and increased diabetes risk. We previously showed that acute high-dose TCDD exposure (20 μg/kg) decreased plasma insulin levels in both male and female mice in vivo; however, effects on glucose homeostasis were sex-dependent. The purpose of this study was to determine whether prolonged exposure to a physiologically relevant dose of TCDD impairs beta cell function and/or glucose homeostasis in a sex-dependent manner in either chow-fed or HFD-fed mice.MethodsMale and female mice were exposed to 20 ng/kg/d TCDD 2x/week for 12 weeks, and simultaneously fed a chow or 45% high-fat diet (HFD). Glucose metabolism was assessed by glucose and insulin tolerance tests throughout the study. Islets were isolated from females at 12 weeks for Tempo-Seq® analysis.ResultsLow-dose TCDD exposure did not lead to adverse metabolic consequences in chow-fed male or female mice, or in HFD-fed males. However, TCDD accelerated the onset of HFD-induced hyperglycemia and impaired glucose-induced plasma insulin levels in female mice. In addition, islet TempO-Seq® analysis showed that TCDD exposure promoted abnormal changes to endocrine and metabolic pathways in HFD-fed females.ConclusionsOur data suggest that TCDD exposure is more deleterious when combined with HFD-feeding in female mice, and that low-dose TCDD exposure increases diabetes susceptibility in females.

scholarly journals Prenatal low-dose methyltestosterone, but not dihydrotestosterone, treatment induces penile formation in female mice and guinea pigs†

2020 ◽  
Vol 102 (6) ◽  
pp. 1248-1260
Author(s):  
Shanshan Wang ◽  
John Lawless ◽  
Zhengui Zheng
Keyword(s):  
Guinea Pigs ◽  
Low Dose ◽  
Androgen Receptors ◽  
Nuclear Translocation ◽  
Sex Differentiation ◽  
External Genitalia ◽  
Gene Expressions ◽  
Female Mice ◽  
Genital Tubercle

Abstract Genital tubercle has bisexual potential before sex differentiation. Females exposed to androgen during sex differentiation show masculinized external genitalia, but the effects of different androgens on tubular urethral and penile formation in females are mostly unknown. In this study, we compared the masculinization effects of commonly used androgens methyltestosterone, dihydrotestosterone, and testosterone on the induction of penile formation in females. Our results suggested that prenatal treatment with low doses of methyltestosterone, but not same doses of dihydrotestosterone or testosterone, could induce penile formation in female mice. The minimum dose of dihydrotestosterone and testosterone for inducing tubular urethral formation in female mice was, respectively, 50 and 20 times higher than that of methyltestosterone. In vivo methyltestosterone treatment induced more nuclear translocation of androgen receptors in genital tubercles of female mice, affected Wnt signaling gene expressions, and then led to similar patterns of cell proliferation and death in developing genital tubercles to those of control males. We further revealed that low-dose methyltestosterone, but not same dose of dihydrotestosterone or testosterone, treatment induced penile formation in female guinea pigs. Exposure of female mouse genital tubercle organ culture to methyltestosterone, dihydrotestosterone, or testosterone could induce nuclear translocation of androgen receptors, suggesting that the differential effect of the three androgens in vivo might be due to the hormonal profile in mother or fetus, rather than the local genital tissue. To understand the differential role of these androgens in masculinization process involved is fundamental to androgen replacement therapy for diseases related to external genital masculinization.

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