title: Effect of testosterone deficiency on cholesterol metabolism in pigs fed a high-fat and high-cholesterol diet.
abstract: BACKGROUND
  Testosterone deficiency is associated with increased serum cholesterol levels. However, how testosterone deficiency precisely affects cholesterol metabolism remains unclear. Therefore, in the current study, we examined the effect of testosterone deficiency on cholesterol metabolism and liver gene expression in pigs fed a high-fat and high-cholesterol (HFC) diet.
  
  
  METHODS
  Sexually mature male miniature pigs (6-7 months old) were randomly divided into 3 groups as follows: intact male pigs fed an HFC diet (IM+HFC), castrated male pigs fed an HFC diet (CM+HFC), and castrated pigs with testosterone replacement fed an HFC diet (CM+HFC+T). Serum testosterone levels and lipid profiles were measured, and gene expression levels associated with hepatic cholesterol metabolism were determined. Furthermore, total hepatic cholesterol contents and the activities of enzymes mediating hepatic cholesterol metabolism were measured.
  
  
  RESULTS
  Serum testosterone levels were significantly decreased in CM+HFC pigs, and testosterone replacement attenuated castration-induced testosterone deficiency. Castration significantly increased the serum levels of total cholesterol, low-density lipoprotein cholesterol and triglycerides, as well as hepatic lipid contents in pigs fed an HFC diet. Compared with IM+HFC and CM+HFC+T pigs, low-density lipoprotein receptor (LDLR) mRNA expression and protein levels were significantly decreased in the livers of CM+HFC pigs. In contrast, we found that compared with IM+HFC pigs, hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA and serum PCSK9 protein levels were significantly increased in CM+HFC pigs. Moreover, testosterone treatment reversed the increase in PCSK9 expression in CM+HFC pigs. However, neither castration nor testosterone replacement affected the expression of the other hepatic genes that were tested.
  
  
  CONCLUSIONS
  This study demonstrated that castration-induced testosterone deficiency caused severe hypercholesterolemia in pigs fed an HFC diet; furthermore, these effects could be reversed by testosterone replacement therapy. Altered hepatic PCSK9 and LDLR expression, resulting in reduced LDL-cholesterol clearance, may contribute to the increased serum cholesterol levels induced by testosterone deficiency and an HFC diet. These results deepen our understanding of the underlying molecular mechanisms that mediate the effects of testosterone deficiency on cholesterol metabolism.
authors.affiliation: Laboratory Animal Research Center, Zhejiang Chinese Medical University, Hangzhou, 310053, China. zwc_zjtcm@hotmail.com.
authors.forename: Zhaowei
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Reproduction Medicine Center, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China. xihaitao2001@163.com.
authors.forename: Haitao
authors.initials: H
authors.lastname: Xi
authors.affiliation: Laboratory Animal Research Center, Zhejiang Chinese Medical University, Hangzhou, 310053, China. yongmp@163.com.
authors.forename: Yongming
authors.initials: Y
authors.lastname: Pan
authors.affiliation: College of Animal Science, Zhejiang University, Hangzhou, 310025, China. xiaolingjiang@zju.edu.cn.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Laboratory Animal Research Center, Zhejiang Chinese Medical University, Hangzhou, 310053, China. chl810@foxmail.com.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Laboratory Animal Research Center, Zhejiang Chinese Medical University, Hangzhou, 310053, China. cyq810@hotmail.com.
authors.forename: Yueqin
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Laboratory Animal Research Center, Zhejiang Chinese Medical University, Hangzhou, 310053, China. zjzygyz@126.com.
authors.forename: Keyan
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Laboratory Animal Research Center, Zhejiang Chinese Medical University, Hangzhou, 310053, China. 616884746@qq.com.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: Laboratory Animal Research Center, Zhejiang Chinese Medical University, Hangzhou, 310053, China. labanim1983@sina.com.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Xu
authors.affiliation: Laboratory Animal Research Center, Zhejiang Chinese Medical University, Hangzhou, 310053, China. cml-zjtcm@hotmail.com.
authors.forename: Minli
authors.initials: M
authors.lastname: Chen
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D008076:Cholesterol, HDL / Q000032:analysis / Q000097:blood; D008078:Cholesterol, LDL / Q000032:analysis / Q000097:blood; D059305:Diet, High-Fat / Q000009:adverse effects*; D015870:Gene Expression / Q000187:drug effects; D006937:Hypercholesterolemia / Q000139:chemically induced / Q000209:etiology; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008297:Male; D009919:Orchiectomy / Q000662:veterinary; D060888:Real-Time Polymerase Chain Reaction; D013552:Swine; D013556:Swine, Miniature; D013739:Testosterone / Q000097:blood / Q000172:deficiency*; D014280:Triglycerides / Q000032:analysis / Q000097:blood
chemical_list: D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D014280:Triglycerides; D013739:Testosterone; D002784:Cholesterol