Sumoylated PPARalpha mediates sex-specific gene repression and protects the liver from estrogen-induced toxicity in mice.
نویسندگان
چکیده
As most metabolic studies are conducted in male animals, understanding the sex specificity of the underlying molecular pathways has been broadly neglected; for example, whether PPARs elicit sex-dependent responses has not been determined. Here we show that in mice, PPARalpha has broad female-dependent repressive actions on hepatic genes involved in steroid metabolism and immunity. In male mice, this effect was reproduced by the administration of a synthetic PPARalpha ligand. Using the steroid oxysterol 7alpha-hydroxylase cytochrome P4507b1 (Cyp7b1) gene as a model, we elucidated the molecular mechanism of this sex-specific PPARalpha-dependent repression. Initial sumoylation of the ligand-binding domain of PPARalpha triggered the interaction of PPARalpha with GA-binding protein alpha (GABPalpha) bound to the target Cyp7b1 promoter. Histone deacetylase and DNA and histone methylases were then recruited, and the adjacent Sp1-binding site and histones were methylated. These events resulted in loss of Sp1-stimulated expression and thus downregulation of Cyp7b1. Physiologically, this repression conferred on female mice protection against estrogen-induced intrahepatic cholestasis, the most common hepatic disease during pregnancy, suggesting a therapeutic target for prevention of this disease.
منابع مشابه
Peroxisome proliferator-activated receptor alpha protects against glomerulonephritis induced by long-term exposure to the plasticizer di-(2-ethylhexyl)phthalate.
Safety concerns about di-(2-ethylhexyl)phthalate (DEHP), a plasticizer and a probable endocrine disruptor, have attracted considerable public attention, but there are few studies about long-term exposure to DEHP. DEHP toxicity is thought to involve peroxisome proliferator-activated receptor alpha (PPARalpha), but this contention remains controversial. For investigation of the long-term toxicity...
متن کاملHepatoprotective effects of licochalcone B on carbon tetrachloride-induced liver toxicity in mice
Objective(s): The objective of this study was to investigate the hepatoprotective effect of licochalcone B (LCB) in a mice model of carbon tetrachloride (CCl4)-induced liver toxicity. Materials and Methods: Hepatotoxicity was induced in mice by a single subcutaneous injection (SC) of CCl4. The LCB was administered orally once a day for seven days (PO) as pretreatment at three doses of 1, 5, and...
متن کاملThe effect of low dose amphetamine in rotenone-induced toxicity in a mice model of Parkinson’s disease
Objective(s): The effects of low dose amphetamine on oxidative stress and rotenone-induced neurotoxicity and liver injury were examined in vivo in a mice model of Parkinson’s disease. Materials and Methods: Male mice were treated with rotenone (1.5 mg/kg, every other day for two weeks, subcutaneously). Mice received either the vehicle or...
متن کاملPeroxisome proliferator-activated receptor alpha mediates the effects of high-fat diet on hepatic gene expression.
Peroxisome proliferator-activated receptors (PPARs) are transcription factors involved in the regulation of numerous metabolic processes. The PPARalpha isotype is abundant in liver and activated by fasting. However, it is not very clear what other nutritional conditions activate PPARalpha. To examine whether PPARalpha mediates the effects of chronic high-fat feeding, wild-type and PPARalpha nul...
متن کاملHydroalcoholic extract of Iranian Caper leaves protects hepatic toxicity by suppressing oxidative stress in mice
Capparis spinosa L. (Caper) is known as an aromatic plant, commonly used in Mediterranean diet, possessing numerous antioxidant compounds such as phenols, rutin, tocopherols, carotenoids, and vitamin C in its leaves. Thus, the purpose of the present study was to investigate the effects of Iranian Caper leaves extract on oxidative stress caused by CCl4 in mice liver. In this study, a total numbe...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- The Journal of clinical investigation
دوره 119 10 شماره
صفحات -
تاریخ انتشار 2009