ABSTRACT
BACKGROUND/AIMS: Both the farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) play important roles in lipid metabolism and atherosclerosis. We investigated the interaction between FXR and PPARgamma. METHODS: Apolipoprotein E knockout (ApoE-/-) mice and FXR knockout (FXR-/-) mice were crossed to generate ApoE-/-FXR-/- mice. The mice were divided into ApoE-/-, ApoE-/-FXR-/-, and ApoE-/-FXR-/- + pioglitazone groups. All mice were fed a high-fat, high-cholesterol diet for 12 weeks. The ApoE-/-FXR-/- + pioglitazone group was also treated with pioglitazone, 20 mg/kg body weight. Body weight, blood glucose level, lipid profile, and liver enzyme levels were measured. To evaluate atherosclerotic lesions, the aorta was stained with Oil red O. RESULTS: There were no differences in body weight or blood glucose level among the three groups. The serum lipid concentration and liver enzyme levels increased in the ApoE-/-FXR-/- group compared with the ApoE-/- group (p < 0.01). The ApoE-/-FXR-/- + pioglitazone group had lower high-density lipoprotein (HDL) (55 +/- 4 vs. 28 +/- 2 mg/dL, p < 0.01) and low-density lipoprotein (LDL) (797 +/- 26 vs. 682 +/- 47 mg/dL, p = 0.04) cholesterol than the ApoE-/-FXR-/- group. The respective percentages of aortic atherosclerotic plaques in the ApoE-/-, ApoE-/-FXR-/-, and ApoE-/-FXR-/- + pioglitazone groups were 2.7 +/- 0.2%, 7.7 +/- 1.2%, and 18.6 +/- 1.0%. In ApoE-/-FXR-/- mice, the administration of pioglitazone significantly increased the number of atherosclerotic lesions (p = 0.02). CONCLUSIONS: Pioglitazone increased the number of atherosclerotic plaques in ApoE-/-FXR-/- mice. This suggests that when FXR is inhibited, the activation of PPARgamma can aggravate atherosclerosis.
Subject(s)
Animals , Mice , Aorta , Apolipoproteins , Atherosclerosis , Blood Glucose , Body Weight , Cholesterol , Diet , Lipid Metabolism , Lipoproteins , Liver , Peroxisome Proliferator-Activated Receptors , Peroxisomes , Plaque, Atherosclerotic , PPAR gamma , Receptors, Cytoplasmic and Nuclear , ThiazolidinedionesABSTRACT
Bisphenol A (BPA) has been reported to possess hepatic toxicity. We investigated the hypothesis that BPA, below the no observed adverse effect level (NOAEL), can induce hepatic damage and mitochondrial dysfunction by increasing oxidative stress in the liver. Two doses of BPA, 0.05 and 1.2 mg/kg body weight/day, were administered intraperitoneally for 5 days to mice. Both treatments impaired the structure of the hepatic mitochondria, although oxygen consumption rate and expression of the respiratory complex decreased only at the higher dose. The hepatic levels of malondialdehyde (MDA), a naturally occurring product of lipid peroxidation, increased, while the expression of glutathione peroxidase 3 (GPx3) decreased, after BPA treatment. The expression levels of proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) also increased. In HepG2 cells, 10 or 100 nM of BPA also decreased the oxygen consumption rate, ATP production, and the mitochondrial membrane potential. In conclusion, doses of BPA below the NOAEL induce mitochondrial dysfunction in the liver, and this is associated with an increase in oxidative stress and inflammation.
Subject(s)
Animals , Humans , Male , Mice , Adenosine Triphosphate/metabolism , Glutathione Peroxidase/metabolism , Hep G2 Cells , Inflammation/chemically induced , Injections, Intraperitoneal , Interleukin-6/metabolism , Lipid Peroxidation/drug effects , Liver/drug effects , Malondialdehyde/metabolism , Membrane Potential, Mitochondrial/drug effects , Mice, Inbred C57BL , Mitochondria/drug effects , Oxidative Stress/drug effects , Oxygen Consumption/drug effects , Phenols/toxicity , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND AND OBJECTIVES: Excretion of bile acid and free cholesterol of bile was important to maintain cholesterol homeostasis. ATP-binding cassette transporter G5 (ABCG5) and G8 (ABCG8) promoted biliary cholesterol excretion. In previous study, hepatic secretion of cholesterol and ABCG5/G8 expression are strongly stimulated in hypophysectomized rats during treatment with thyroid hormone. In this study, we aimed to evaluate the effect of thyroid hormone to expression of ABCG5 and G8 in mouse liver. MATERIALS AND METHODS: We administered thyroid hormone (T3) to C57BL/6 mice and then RNA and protein was isolated from liver. We isolated primary hepatocyte and administered T3 to evaluate in vitro effect. HepG2 cells were cotransfected with either a control plasmid or expression plasmids for human thyroid hormone receptor (hTR)beta/human retinoid X receptor (hRXR)alpha or human liver X receptor (hLXR)alpha in combination with reporter plasmids TK-LXRE3-LUC with or without T3. RESULTS: Serum total cholesterol was decreased after 5 days of T3 treatment. Expression of ABCG5/8 mRNA and ABCG5 protein was increased after T3 treatment. In primary hepatocytes, T3 also increased ABCG5/8 mRNA expression. LXRalpha mRNA was not increased by T3. However, when we cotransfected liver X receptor response element (LXRE) construct and TRbeta/RXRalpha with T3, the activity of LXRE containing construct was markedly increased. CONCLUSION: We confirmed that thyroid hormone increased expression of ABCG5/8. This result suggested that thyroid hormone played an important role in decreasing serum cholesterol through bile excretion.
Subject(s)
Animals , Humans , Mice , Rats , Bile , Cholesterol , Hep G2 Cells , Hepatocytes , Homeostasis , Liver , Orphan Nuclear Receptors , Plasmids , Receptors, Thyroid Hormone , Response Elements , Retinoid X Receptors , RNA , RNA, Messenger , Thyroid Gland , Thyroid HormonesABSTRACT
BACKGROUND: Bile acids were important for the regulation of cholesterol homeostasis. Thyroid hormone increased the expression of CYP7A1 (cholesterol 7alpha-hydroxylase), catalyzing the first step in the biosynthesis of bile acids. However, the effect of thyroid hormone on bile acid export has not been previously assessed. The principal objective of this study is to evaluate the effects of thyroid hormone on the bile salt export pump (BSEP). METHODS: Thyroid hormone, T3 (1 mg/g) was administered to male mice via intraperitoneal injection. After 6 hours and 5 days of T3 treatment, we measured serum total and LDL cholesterol and hepatobiliary bile acid concentrations. We assessed the changes associated with bile acid synthesis and transport. In order to evaluate the direct effect of thyroid hormone, we assessed the changes in the levels of BSEP protein after T3 administration in human hepatoma cells. RESULTS: Serum total and LDL cholesterol were reduced and hepatobiliary bile acid concentrations were increased following T3 treatment. Expressions of Cyp7a1 and BSEP mRNA were increased following T3 treatment. The levels of the BSEP protein in the mouse liver as well as in the human hepatoma cells were increased after T3 treatment. CONCLUSION: Thyroid hormone can regulate LDL cholesterol metabolism. It increases bile acid synthesis and the excretion of bile acids via increased BSEP expression.