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

in Journal of Endocrinology
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  • 1 T Seidu, Physiology and Biophysics, Howard University College of Medicine, Washington, United States
  • 2 P McWhorter, Chemistry, Youngstown State University, Youngstown, United States
  • 3 J Myer, Biology, University of Missouri, Columbia, United States
  • 4 R Alamgir, Physiology and Biophysics, Howard University College of Medicine, Washington, United States
  • 5 N Eregha, Physiology and Biophysics, Howard University College of Medicine, Washington, United States
  • 6 D Bogle, Physiology and Biophysics, Howard University College of Medicine, Washington, United States
  • 7 T Lofton, Physiology and Biophysics, Howard University College of Medicine, Washington, United States
  • 8 C Ecelbarger, Medicine, Georgetown University Medical Center, Washington, United States
  • 9 S Andrisse, Physiology and Biophysics, Howard University College of Medicine, Washington, 20059, United States

Correspondence: Stanley Andrisse, Email: stanley.andrisse@howard.edu

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.

 

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