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.
Hyperandrogenemia (HA) and insulin resistance (IR) are hallmarks of polycystic ovary syndrome (PCOS), a common endocrine disorder that affects roughly 1 in 5 women, according to the Rotterdam criteria. These hallmarks are also integral elements of non-alcoholic fatty liver disease (NALFD), a disorder that is common in women with PCOS. In lean female mouse models of dihydrotestosterone (DHT)-induced PCOS, a low dose of DHT promotes IR and hepatic lipogenesis via the androgen receptor (AR), thus resulting in NAFLD (1). However, the molecular mechanism of HA-induced NAFLD has not been determined. We hypothesized that a low dose of DHT would interrupt hepatic lipid metabolism leading to NAFLD. To investigate the role of androgen and AR on a master regulator of lipogenesis, sterol regulatory element-binding protein 1 (SREBP-1), we extracted white adipose tissue (WAT) from lean, female wild-type mice and lean PCOS female mice, aka "DHT mice." Then we analyzed the effect of low-dose DHT on lipogenic protein and gene expression as a control to low-dose DHT's impact on the liver. We accomplished this by performing Western blots and real-time quantitative polymerase chain reaction (qRT-PCR) analysis of the cytosolic lipogenic proteins and gene expression of WAT. A low dose of DHT lowered the active form of SREBP-1 in DHT mice in comparison to the control mice, but there was no significant change in fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), phosphorylated ACC (p-ACC), and the active and inactive forms of SREBP-2. We speculate that the low-dose DHT promotes the translocation of SREBP-1 from the cytosol to the nucleus to influence lipogenic gene expression leading to increased lipogenesis contributing to NAFLD. (1) Andrisse et al., Endocrinology. 2017 Mar 1;158(3):531-544.
Polycystic ovary syndrome (PCOS) affects 10% of women and is hallmarked by hyperandrogenemia (HA), which is also a component of non-alcoholic fatty liver disease (NAFLD). In this project, we aimed to investigate how androgen and androgen receptor (AR) impact a key player of lipogenesis, sterol regulatory element-binding protein 1 (SREBP1). To this end, skeletal muscle from lean, female wild type mice and mice administered dihydrotestosterone (DHT) for one month were extracted and analyzed to determine the effect of low dose DHT on lipogenic cytosolic protein and gene expression. We performed Western blot and real-time quantitative polymerase chain reaction (qRT-PCR) analysis of lipogenic intermediates in homogenates of an energy storage tissue. Skeletal muscle was used as a control. Low-dose DHT lowered the active form of cytosolic SREBP-2 in skeletal muscle. However, FAS and p-ACC protein and mRNA expression levels were unchanged in skeletal muscle. The results indicate that SREBP-2 is the primary SREBP isoform in skeletal muscle but that it is not playing a role in DHT-induced lipogenic gene expression or NAFLD. Thank you to HUCM, JHUSOM, and Georgetown University Medical Center (GUMC) for supporting this work.
ImportanceRetinal vein occlusion is the second most common retinal vascular disease. Bevacizumab was demonstrated in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) to be noninferior to aflibercept with respect to visual acuity in study participants with macular edema due to central retinal vein occlusion (CRVO) or hemiretinal vein occlusion (HRVO) following 6 months of therapy. In this study, the cost-utility of bevacizumab vs aflibercept for treatment of CRVO is evaluated.ObjectiveTo investigate the relative cost-effectiveness of bevacizumab vs aflibercept for treatment of macular edema associated with CRVO or HRVO.Design, Setting, and ParticipantsThis economic evaluation study used a microsimulation cohort of patients with clinical and demographic characteristics similar to those of SCORE2 participants and a Markov process. Parameters were estimated and validated using a split-sample approach of the SCORE2 population. The simulated cohort included 5000 patients who were evaluated 100 times, each with a different set of characteristics randomly selected based on the SCORE2 trial. SCORE2 data were collected from September 2014 October 2019, and data were analyzed from October 2019 to July 2021.InterventionsBevacizumab (followed by aflibercept among patients with a protocol-defined poor or marginal response to bevacizumab at month 6) vs aflibercept (followed by a dexamethasone implant among patients with a protocol-defined poor or marginal response to aflibercept at month 6).Main Outcomes and MeasuresIncremental cost-utility ratio.ResultsThe simulation demonstrated that patients treated with aflibercept will have an expected cost $18 127 greater than those treated with bevacizumab in the year following initiation. When coupled with the lack of clinical superiority over bevacizumab (ie, patients treated with bevacizumab had a gain over aflibercept in visual acuity letter score of 4 in the treated eye and 2 in the fellow eye), these results demonstrate that first-line treatment with bevacizumab dominated aflibercept in the simulated cohort of SCORE2 participants. At current price levels, aflibercept would be considered the preferred cost-effective option only if treatment restored the patient to nearly perfect health.Conclusions and RelevanceWhile there will be some patients with CRVO-associated or HRVO-associated macular edema who will benefit from first-line treatment with aflibercept rather than bevacizumab, given the minimal differences in visual acuity outcomes and large cost differences for bevacizumab vs aflibercept, first-line treatment with bevacizumab is cost-effective for this condition.
Hyperandrogenemia (HA) and insulin resistance (IR) are hallmarks of polycystic ovary syndrome (PCOS), a common endocrine disorder that affects 1 in 10 women. These hallmarks are also integral elements of non-alcoholic liver disease (NALFD), a disorder that is common in women with PCOS. Administering low dose dihydrotestosterone (DHT) induced a lean female mouse model with a PCOS-like phenotype, displaying IR and NAFLD. 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. To investigate the role of androgens on the master regulator of lipogenesis, sterol regulatory element-binding protein 1 (SREBP1), we extracted white adipose tissue (WAT), liver, and skeletal muscle from wild-type, control and low dose DHT female mice; and performed Western blot and real-time quantitative PCR (qRT-PCR) analysis of lipogenic intermediates of the tissue homogenates. Low-dose DHT lowered the active form of cytosolic SREBP1 in the liver and WAT compared to controls. Additionally, low dose DHT lowered inactive SREBP1 in the liver. However, the condition did not alter the levels of the active and inactive forms of SREBP2 in the liver and WAT, though the active form was lowered in skeletal muscle. Further, p-ACC levels were unaltered in liver and WAT. FAS levels were unchanged in WAT and skeletal muscle. Taken together, our findings support the hypothesis that cytosolic SREBP1 decreased due to its translocation to the nucleus, where it regulates lipogenic protein levels. We speculate that low-dose DHT promotes the translocation of SREBP1 from the cytosol to the nucleus to influence lipogenic gene expression leading to increased lipogenesis contributing to NAFLD.
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