RESUMO
The aim of the present study was to identify molecular mechanisms involved in liver fat and cholesterol accumulation in ovariectomised (Ovx) rats fed with high-cholesterol diets. VLDL assembly and bile acid metabolism were specifically targeted. After being either Ovx or sham-operated, the rats were fed a standard diet or a high-fat diet containing 0, 0·25 or 0·5 % cholesterol for 6 weeks. Although Ovx rats exposed to dietary cholesterol intake accumulated the greatest amount of hepatic fat and cholesterol, plasma cholesterol levels were lower (P< 0·05) in these animals than in the corresponding control rats. Accompanying this observation, ovariectomy and dietary cholesterol intake resulted in a down-regulation (P< 0·05) of the expression of genes associated with VLDL assembly, including microsomal TAG transfer protein, diacylglycerol acyltransferase 2, acyl-CoA:cholesterol acyltransferase 2 and apoB-100 as well as genes associated with bile acid metabolism including farnesoid X receptor and bile salt export pump (P< 0·01). These results indicate that high-fat/high-cholesterol diets and ovariectomy concomitantly disrupt hepatic lipid output through defects in VLDL assembly and, most probably, secretion. The results also point to a defect in hepatic bile acid secretion. The present study offers novel insights into intrahepatic lipid metabolism, which may be relevant to metabolic complications found in postmenopausal women.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/metabolismo , Estrogênios/deficiência , Fígado Gorduroso/metabolismo , Metabolismo dos Lipídeos , Lipoproteínas VLDL/biossíntese , Fígado/metabolismo , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Apolipoproteína B-100/metabolismo , Ácidos e Sais Biliares/metabolismo , Proteínas de Transporte/metabolismo , Colesterol na Dieta/efeitos adversos , Colesterol na Dieta/metabolismo , Gorduras na Dieta/efeitos adversos , Regulação para Baixo , Fígado Gorduroso/etiologia , Feminino , Lipoproteínas VLDL/metabolismo , Ovariectomia , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/metabolismo , Esterol O-Aciltransferase/metabolismo , Esterol O-Aciltransferase 2RESUMO
Chlorinated persistent organic pollutants, commonly referred to as organochlorine compounds (OCs), are chemicals of environmental concern that were mostly used historically as pesticides, solvents, flame retardants, and other applications, though some still continue to be produced. OCs accumulate in adipose tissue because of their hydrophobicity. Evidence suggests that OCs modulate adipose tissue metabolism and could affect its development. At the cellular level, the development of adipose tissue is partly controlled by replication of preadipocytes, which may in turn be modulated by contaminants. The aim of this study was to determine whether exposure to specific OCs and to different concentrations, some mimecting those achieved in human tissues that are exposed to chemicals from the environment, affects human preadipocyte proliferation capacity. Human preadipocytes were exposed to various concentrations (3-500 µM) of highly prevalent OCs (PCBs 77, 153 and DDE) for 48 h. At the end of the exposure period, quantification of cell density was assessed by a cell proliferation ELISA assay. Preadipocyte proliferation significantly increased (~28-72%) in response to most of the concentrations of PCB 153 and DDE as compared to the control. These findings suggest that exposure to some OCs and concentrations increase the proliferative capacity of human preadipocytes.
Assuntos
Adipócitos Brancos/fisiologia , Proliferação de Células/efeitos dos fármacos , Hidrocarbonetos Clorados/farmacologia , Diclorodifenil Dicloroetileno/farmacologia , Poluentes Ambientais/farmacologia , Humanos , Inseticidas/farmacologia , Bifenilos Policlorados/farmacologia , Gordura Subcutânea/citologiaRESUMO
Polychlorinated biphenyls (PCBs) have been recognized as metabolic disruptors. The liver plays a pivotal role in detoxification of an organism. Fatty liver results from altered intra-, and extra-hepatic mediators and is associated with increased glucose-related protein 78 (GRP78), commonly used as a marker for endoplasmic reticulum (ER) stress signaling. This pilot study aimed to study the effects of a single exposure on fatty liver metabolic parameters. The objective of the study is to characterize the effects of 3,3',4,4',5-pentachlorobiphenyl (PCB126) on ER stress protein chaperon GRP78 and CCAAT-enhancer-binding protein homologous protein (CHOP) and intra-hepatic mediators such as microsomal triglyceride transfer protein (MTP), sterol regulatory element-binding protein 1c (SREBP1c), and peroxisome proliferator-activated receptor alpha (PPARα), as well as extra-hepatic factors such as non-esterified fatty acid (NEFA) and tumor necrosis factor alpha (TNFα). Hepatic GRP78 mRNA and protein levels, indicating the presence of ER stress, were significantly increased following a single PCB126 exposure in rats. Intra-hepatic mechanisms such as lipoprotein secretion pathway (i.e., MTP), lipogenesis de novo (i.e., SREBP1c), and oxidation (i.e., PPARα) were altered in PCB126-treated rats. In addition, a state of inflammation measured by higher TNFα plasma levels was present in contaminated rats. These data indicate that a single injection of PCB126-modulated expression of GRP78 associated with hepatic ER stress and systemic inflammation in rats.