title: Saturated fatty acid exposure induces androgen overproduction in bovine adrenal cells.
abstract: BACKGROUND
  Polycystic ovary syndrome (PCOS) is mainly defined by hyperandrogenemia, from ovarian and adrenal origin, and is characterized by insulin resistance (IR). Studies found that raising in vivo non-esterified fatty acid (NEFA) levels, which induces lipotoxicity, increases androgen levels and IR. The aim of this study was therefore to determine the effects of in vitro over-exposure to NEFA on androgen synthesis in a bovine adrenocortical cell model.
  
  
  METHODS
  Bovine fasciculata/reticularis cells were cultured for 2days in the absence or presence of ACTH (10nmol/L) or Forskolin (fsk, 10μmol/L), alone or in combination with the saturated fatty acid (FA) palmitate (100μmol/L). Steroid production was measured in medium and corrected for initial cell seeding count. CYP17 protein expression and ERK1/2 phosphorylation were assessed by Western blotting.
  
  
  RESULTS
  Under unstimulated conditions, dehydroepiandrosterone (DHEA) levels were barely detected and no difference was observed after palmitate exposure, which was also the case for CYP17 expression and ERK1/2 phosphorylation. Under stimulation, palmitate exposure increased DHEA production by 38% and 69%, for ACTH and fsk, respectively, as compared to untreated conditions (Ps⩽0.05). In palmitate-treated vs untreated cells, fsk-stimulated ERK1/2 phosphorylation was reduced by 46% (P=0.0047), but stimulated CYP17 expression was not significantly affected.
  
  
  CONCLUSIONS
  In a model of androgen-producing cells, under stimulated conditions, overexposure to saturated FAs significantly increases androgen production and reduces MEK/ERK activation. Therefore, this study is the first to demonstrate that lipotoxicity can directly trigger androgen overproduction in vitro, in addition to its well-described impact on IR, which strongly supports a central role of lipotoxicity in PCOS pathophysiology.
authors.affiliation: Division of Endocrinology, Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Bellanger
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Battista
authors.forename: Guy D
authors.initials: GD
authors.lastname: Fink
authors.forename: Jean-Patrice
authors.initials: JP
authors.lastname: Baillargeon
mesh_terms: D000302:Adrenal Cortex / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D000728:Androgens / Q000096:biosynthesis*; D000818:Animals; D002417:Cattle; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D028421:Isoprostanes / Q000096:biosynthesis; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism
chemical_list: D000728:Androgens; D005230:Fatty Acids, Nonesterified; D028421:Isoprostanes; D013254:Steroid 17-alpha-Hydroxylase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases