title: Differential effects of estrogen/androgen on the prevention of nonalcoholic fatty liver disease in the male rat.
abstract: It is important to clarify the distinct contributions of estrogen/estrogen receptor (ER) and androgen/androgen receptor (AR) signaling and their reciprocal effects on the regulation of hepatic lipid homeostasis. We studied the molecular mechanisms underlying the preventive effects of estradiol (E2), dihydrotestosterone (DHT), or E2+DHT on high-fat diet-induced nonalcoholic fatty liver disease (NAFLD) in an orchidectomized Sprague-Dawley (SD) rat model. E2 is shown to be associated with decreased fatty acid synthesis in hepatic zone 3-specific manner by increasing the phosphorylation of acetyl coenzyme-A carboxylase via an ERα-mediated pathway. DHT is shown to be associated with decreased lipid accumulation and cholesterol synthesis in a hepatic zone 1-specific manner by increasing expression of carnitine palmitotyltransferase1 and phosphorylation of 3-hydroxy-3-methyl-glutaryl-CoA reductase via an AR-mediated pathway. E2+DHT showed an additive positive effect and normalized all three impaired zones of the liver. Gene expression changes in human severe liver steatosis were similar to those of experimental rat NAFLD. Steroids reversed the histopathological NAFLD changes, likely by decreasing fatty acid and cholesterol synthesis and increasing β-oxidation. The diverse steroid effects (ER/AR) on NAFLD prevention in male rats indicate the potential applicability of ER/AR modulators for NAFLD treatment.
authors.affiliation: State Key Laboratory of Agro-Biotechnology, China Agricultural University, Beijing, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Yuanwu
authors.initials: Y
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.forename: Hongwen
authors.initials: H
authors.lastname: Zhang
authors.forename: Jihua
authors.initials: J
authors.lastname: Wu
authors.forename: Nafis
authors.initials: N
authors.lastname: Rahman
authors.forename: Yangdong
authors.initials: Y
authors.lastname: Guo
authors.forename: Defa
authors.initials: D
authors.lastname: Li
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Ilpo
authors.initials: I
authors.lastname: Huhtaniemi
authors.forename: Suk Ying
authors.initials: SY
authors.lastname: Tsang
authors.forename: George F
authors.initials: GF
authors.lastname: Gao
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Li
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000368:Aged; D000728:Androgens / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis; D059305:Diet, High-Fat / Q000009:adverse effects; D013196:Dihydrotestosterone / Q000097:blood / Q000494:pharmacology*; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D004958:Estradiol / Q000097:blood / Q000172:deficiency / Q000494:pharmacology*; D004967:Estrogens / Q000097:blood / Q000172:deficiency / Q000494:pharmacology*; D005227:Fatty Acids / Q000096:biosynthesis; D005234:Fatty Liver / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D009919:Orchiectomy / Q000009:adverse effects; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013739:Testosterone / Q000172:deficiency; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000728:Androgens; D004967:Estrogens; D005227:Fatty Acids; D007375:Interleukin-1; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D014409:Tumor Necrosis Factor-alpha; D013196:Dihydrotestosterone; D013739:Testosterone; D004958:Estradiol; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D000103:Acetyl-CoA Carboxylase