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.
Highlights
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
A 2.5-month high-fat diet (HFD) increased the body and liver weights compared with normal diet ORX controls (P < 0.05) (Table 3)
E2, DHT, and E2+DHT treatments significantly increased the phosphorylation of the rate-limiting enzyme in de novo fatty acid synthesis, Acetyl-CoA carboxylase (ACC) (P-ACC), compared with HFD controls (Fig. 3A and supplementary Fig. IV), it seemed that ACC enzyme was not regulated at the level of gene expression by DHT (Figs. 2C and 3A)
Summary
Two-month-old, male, ORX SD rats (200 ± 20 g) (Vital-River, Beijing, China) were fed with normal diet (ND; n = 10) or high-fat diet (HFD; n = 30 per group). HFD ORX rats received vehicle (corn oil) or E2, DHT, or E2+DHT treatment once daily subcutaneously for 75 days starting 7 days after being orchidectomized (n = 30 per group). We had wild-type, gonad-intact SD rats on HFD that received vehicle (corn oil) or E2, DHT, or E2+DHT (n = 6 per group) as an internal control group for the ORX rats. The 3.0 mg/kg/d dosage of DHT was chosen because it was shown that this dosage can restore the weight of the ventral prostate (VP) in ORX rats (control: 0.062 ± 0.13 g/VP; ORX: 0.02 ± 0.01 g/VP; DHT: 0.070 ± 0.32 g/VP). MO). 4,4,4′-(4-propyl[1H]pyrazole-1,3,5-triyl) triphenol (PPT; an ER␣ selective agonist) and 2,3-bis(4-hydroxyphenyl) propionitrile (DPN; an ER selective agonist) were purchased from Tocris Biosciences (Ellisville, MO)
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