Sex Difference in Hepatic Peroxisome Proliferator-Activated Receptor α Expression: Influence of Pituitary and Gonadal Hormones

Abstract

Peroxisome proliferator-activated receptor (PPAR) alpha is a nuclear receptor that is mainly expressed in tissues with a high degree of fatty acid oxidation such as liver, heart, and skeletal muscle. Unsaturated fatty acids, their derivatives, and fibrates activate PPARalpha. Male rats are more responsive to fibrates than female rats. We therefore wanted to investigate if there is a sex difference in PPARalpha expression. Male rats had higher levels of hepatic PPARalpha mRNA and protein than female rats. Fasting increased hepatic PPARalpha mRNA levels to a similar degree in both sexes. Gonadectomy of male rats decreased PPARalpha mRNA expression to similar levels as in intact and gonadectomized female rats. Hypophysectomy increased hepatic PPARalpha mRNA and protein levels. The increase in PPARalpha mRNA after hypophysectomy was more pronounced in females than in males. GH treatment decreased PPARalpha mRNA and protein levels, but the sex-differentiated secretory pattern of GH does not determine the sex-differentiated expression of PPARalpha. The expression of PPARalpha mRNA in heart or soleus muscle was not influenced by gender, gonadectomy, hypophysectomy, or GH treatment. In summary, pituitary-dependent hormones specifically regulate hepatic PPARalpha expression. Sex hormones regulate the sex difference in hepatic PPARalpha levels, but not via the sexually dimorphic GH secretory pattern.

Transcriptome analyses demonstrate that Peroxisome Proliferator-Activated Receptor α (PPARα) activity of an ultraviolet absorber, 2-(2’-hydroxy-3’,5’-di-tert-butylphenyl)benzotriazole, as possible mechanism of their toxicity and the gender differences

“…In particular, on PND 35, the PPARα mRNA level in males was nearly three times higher than that in females. Consequently, the results of present study of the PPARα mRNA expression level in postnatal male and female rats are consistent with the previous study reported by Jalouli et al (2003).…”

“…Several studies have reported that, in rats, males are more responsive compared with females to various effects of peroxisome proliferators (Amacher et al, 1997;Gray and de la Iglesia, 1984;Kawashima et al, 1989aKawashima et al, , 1989bSvoboda et al, 1969). In addition, Jalouli et al (2003) reported that hepatic PPARα mRNA and protein levels were higher in males than in females and castration of male and female rats markedly reduced the sex-related difference in hepatic PPARα mRNA expression.…”

Role of CYP27A in cholesterol and bile acid metabolism

“…Sex differences in fatty acid metabolism are well known, including in the expression of PPAR␣, which has lower basal expression in females (46). The increase in expression of the PPAR target gene Cpt1 in female homozygous livers suggests an adaptation to cyp27A deficiency by specifically increasing hepatic mitochondrial fatty acid oxidation.…”

Peroxisome Proliferator‐Activated Receptors: Potential Therapeutic Targets in Lung Disease?

“…For PPARa, upregulation in rat liver occurs in a tissue-specific manner in response to fasting, glucocorticoids, and testosterone. [57][58][59] Elevated triglycerides, glucocorticoids (dexamethasone), and PPARa ligands themselves (fibrates) also upregulate liver levels of PPARa. 58,60 Moreover, PPARa expression is upregulated by HMG CoA reductase inhibitors (statins) in rat hepatocytes and human umbilical vein endothelial cells (HUVECs).…”

“…58,60 Moreover, PPARa expression is upregulated by HMG CoA reductase inhibitors (statins) in rat hepatocytes and human umbilical vein endothelial cells (HUVECs). 61 Conversely, PPARa is downregulated by growth hormone, 57 hypoxia, 22 and TNF-a. 62 For PPARg, gene expression is increased in numerous cell types by multiple factors, including cytokines (TNF-a, IL-1b, IL-4), 7 statins, 63 butyrate, 24 cross-linking of IgE receptors on mast cells, 36 and the anti-inflammatory flavinoid amentoflavone.…”