Abstract
Objective
Although low serum testosterone (T) is associated with metabolic disorders, the mechanism
of this association is unclear. The objective of the present study was to investigate
the combined effects of T deficiency and a high-fat diet (HFD) on hepatic lipid homeostasis
in mice.
Materials/Methods
Orchiectomized (ORX) mice and sham-operated (SHAM) mice were randomly divided into
five groups: SHAM mice fed a standard diet (SD), SHAM mice fed HFD, ORX mice fed SD,
ORX mice fed HFD, and ORX mice fed HFD with T supplementation. After 4 weeks of treatment, we investigated the synthesis and secretion of lipids in the liver
and detailed serum lipoprotein profiles in each group.
Results
ORX mice fed HFD showed increased hepatic steatosis, markedly decreased serum triglyceride
(TG) and TG-VLDL content, and increased serum very small-LDL content. Gene expression
analysis revealed that ORX mice fed HFD showed significantly decreased expression
of microsomal triglyceride transfer protein, lipin-1, peroxisome proliferator-activated
receptor (PPAR)-α and PPAR-γ coactivator 1-α, and significantly increased sterol regulatory
element-binding protein-1, diacylglycerol acyltransferase-2 and fatty acid synthase.
Reduction of hepatic AMPK phosphorylation was observed in ORX mice fed HFD. These
perturbations in ORX mice fed HFD were normalized to the levels of SHAM mice fed HFD
by T supplementation.
Conclusion
T deficiency is associated with failure of lipid homeostasis mediated by altered expression
of genes involved in hepatic assembly and secretion of lipids.
Abbreviations:
T (testosterone), AR (androgen receptor), HFD (high-fat diet), SD (standard diet), ORX (orchiectomized), SHAM (sham-operated), PPAR (peroxisome proliferator-activated receptor), SREBP-1 (sterol regulatory element-binding protein 1), DGAT-2 (diacylglycerol acyltransferase 2), FAS (fatty acid synthase), MTP (microsomal transfer protein), Arf-1 (ADP-ribosylation factor-1), PGC-1α (PPAR-γ coactivator 1-α), HPLC (high-performance liquid chromatography), RT-PCR (reverse transcription-polymerase chain reaction)Keywords
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References
- ISA, ISSAM and EAU recommendations for the investigation, treatment and monitoring of late-onset hypogonadism in males: scientific background and rationale.Aging Male. 2005; 8: 59-74
- Castration and diabetes..Diabetes Care. 2000; 23: 1032-1033
- Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men.Diabetes Care. 2004; 27: 1036-1041
- Low serum testosterone concentration in middle-aged men with type 2 diabetes.Endocr J. 2007; 54: 871-877
- Hepatic steatosis is associated with low serum testosterone and high serum DHEAS levels in men.Int J Androl. 2010; 33: 45-53
- A low level of serum total testosterone is independently associated with nonalcoholic fatty liver disease.BMC Gastroenterol. 2012; 12: 69
- Androgen receptor null male mice develop late-onset obesity caused by decreased energy expenditure and lipolytic activity but show normal insulin sensitivity with high adiponectin secretion.Diabetes. 2005; 54: 1000-1008
- Androgens and metabolic syndrome: lessons from androgen receptor knock out (ARKO) mice.J Steroid Biochem Mol Biol. 2008; 109: 254-257
- Increased hepatic steatosis and insulin resistance in mice lacking hepatic androgen receptor.Hepatology. 2008; 47: 1924-1935
- Effects of castration and testosterone administration on serum lipoproteins and their apoproteins in male spontaneously hypertensive rat.Endocrinology. 1986; 118: 1787-1794
- Atherosclerosis is enhanced by testosterone deficiency and attenuated by CETP expression in transgenic mice.J Lipid Res. 2006; 47: 1526-1534
- Dihydrotestosterone treatment results in obesity and altered lipid metabolism in orchidectomized mice.Obesity. 2006; 14: 662-672
- Androgen receptor-dependent and independent atheroprotection by testosterone in male mice.Endocrinology. 2010; 151: 5428-5437
- Androgen receptor expression of proliferating basal and luminal cells in adult murine ventral prostate.J Endocrinol. 1999; 162: 341-350
- Liquid chromatography–tandem mass spectrometry (LC-MS/MS) assay for simultaneous measurement of salivary testosterone and cortisol in healthy men for utilization in the diagnosis of late-onset hypogonadism in males.Endocr J. 2009; 56: 1083-1093
- A simple method for the isolation and purification of total lipides from animal tissues..J Biol Chem. 1957; 226: 497-509
- A new on-line dual enzymatic method for simultaneous quantification of cholesterol and triglycerides in lipoproteins by HPLC.J Lipid Res. 2002; 43: 805-814
- The alpha-glucosidase inhibitor acarbose reduces the net electronegative charge of low-density lipoprotein in patients with newly diagnosed type 2 diabetes.Clin Chim Acta. 2008; 390: 110-114
- Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method.Methods. 2001; 25: 402-440
- Identification and characterization of endoplasmic reticulum stress-induced apoptosis in vivo.Methods Enzymol. 2008; 442: 395-419
- 17β-Estradiol attenuates saturated fatty acid diet-induced liver injury in ovariectomized mice by up-regulating hepatic senescence marker protein-30.Biochem Biophys Res Commun. 2011; 415: 252-257
- Role of resistin in diet-induced hepatic insulin resistance.J Clin Invest. 2004; 114: 232-239
- The PPARβ/δ activator GW501516 prevents the down-regulation of AMPK caused by a high-fat diet in liver and amplifies the PGC-1α-Lipin 1-PPARα pathway leading to increased fatty acid oxidation.Endocrinology. 2011; 152: 1848-1859
- Recent progress in understanding protein and lipid factors affecting hepatic VLDL assembly and secretion.Nutr Metab. 2010; 7: 35
- An MTP inhibitor that normalizes atherogenic lipoprotein levels in WHHL rabbits.Science. 1998; 282: 751-754
- Knockout of the abetalipoproteinemia gene in mice: reduced lipoprotein secretion in heterozygotes and embryonic lethality in homozygotes.Proc Natl Acad Sci USA. 1998; 95: 8686-8691
- Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice.J Clin Invest. 1999; 103: 1287-1288
- Hepatic overexpression of microsomal triglyceride transfer protein (MTP) results in increased in vivo secretion of VLDL triglycerides and apolipoprotein B.J Lipid Res. 1999; 40: 2134-2139
- Adenovirus-mediated overexpression of microsomal triglyceride transfer protein (MTP): mechanistic studies on the role of MTP in apolipoprotein B-100 biogenesis.Biochemistry. 1999; 38: 7532-7544
- Analysis of transcriptome and metabolome profiles alterations in fatty liver induced by high-fat diet in rat.Metabolism. 2010; 59: 554-560
- Sterol regulatory element-binding protein negatively regulates microsomal triglyceride transfer protein gene transcription.J Biol Chem. 1999; 274: 24714-24720
- The level and compartmentalization of phosphatidate phosphatase-1 (lipin-1) control the assembly and secretion of hepatic VLDL.J Lipid Res. 2009; 50: 47-58
- Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) stimulates VLDL assembly through activation of cell death-inducing DFFA-like effector B (CideB).J Biol Chem. 2010; 285: 25996-26004
- Testosterone modulates gene expression pathways regulating nutrient accumulation, glucose metabolism and protein turnover in mouse skeletal muscle.Int J Androl. 2011; 34: 55-68
- Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity.Proc Natl Acad Sci USA. 2000; 97: 12735-12740
- Estrogen replacement reverses the hepatic steatosis phenotype in the male aromatase knockout mouse.Endocrinology. 2004; 145: 1842-1848
Article info
Publication history
Published online: January 18, 2013
Accepted:
December 10,
2012
Received:
September 29,
2012
Identification
Copyright
© 2013 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
