-
[show abstract]
[hide abstract]
ABSTRACT: The beneficial effects of rosiglitazone on non-alcoholic fatty liver disease (NAFLD) have been reported. Rosiglitazone treatment stimulates the production of adiponectin, an insulin-sensitizing adipokine with hepatoprotective functions. The present study aims to investigate the hepatic actions of rosiglitazone in mice without adiponectin.
NAFLD was induced in wild type and adiponectin knockout (AKO) mice by high-fat diet feeding. After rosiglitazone treatment, mice were subjected to evaluations on systemic insulin sensitivity, lipid profiles, hepatic steatosis, and inflammation, as well as the expression and activity of key molecules involved in energy metabolism and mitochondrial functions.
Rosiglitazone treatment prevented hepatic inflammation and reduced the expression of pro-inflammatory cytokines in livers of wild type mice. In contrast, in livers of AKO mice, the same treatment induced severe hepatomegaly and microvesicular hepatosteatosis, and caused abnormal accumulation of fatty acyl CoA, glycogen, and their intermediate metabolites. Compared to wild type littermates, the anti-inflammatory and the mitochondria-stimulatory activity of rosiglitazone were largely attenuated in AKO mice. Replenishment with either adiponectin or uncoupling protein 2 (UCP2) significantly reduced fatty acyl CoA accumulation and increased mitochondrial activities in livers of rosiglitazone-treated AKO mice. In addition, adiponectin, but not UCP2, promoted the activation of glycogen synthase kinase 3beta (GSK3beta), a key molecule involved in regulating glycogen homeostasis.
Rosiglitazone elicits its protective functions against NAFLD largely through the induction of adiponectin, which prevents mitochondria stresses by promoting GSK3beta activation and UCP2 upregulation, two pathways coordinating the glucose and lipid metabolism in liver.
Journal of Hepatology 12/2010; 53(6):1108-16. · 9.26 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Adiponectin is an adipocyte-derived hormone with a wide range of beneficial effects on obesity-related medical complications. Numerous epidemiological investigations in diverse ethnic groups have identified a lower adiponectin level as an independent risk factor for nonalcoholic fatty liver diseases and liver dysfunctions. Animal studies have demonstrated that replenishment of adiponectin protects against various forms of hepatic injuries, suggesting it to be a potential drug candidate for the treatment of liver diseases. This study was designed to investigate the cellular and molecular mechanisms underlying the hepatoprotective effects of adiponectin. Our results demonstrated that in adiponectin knockout (ADN-KO) mice, there was a preexisting condition of hepatic steatosis and mitochondrial dysfunction that might contribute to the increased vulnerabilities of these mice to secondary liver injuries induced by obesity and other conditions. Adenovirus-mediated replenishment of adiponectin depleted lipid accumulation, restored the oxidative activities of mitochondrial respiratory chain (MRC) complexes, and prevented the accumulation of lipid peroxidation products in ADN-KO mice but had no obvious effects on mitochondrial biogenesis. The gene and protein levels of uncoupling protein 2 (UCP2), a mitochondrial membrane transporter, were decreased in ADN-KO mice and could be significantly up-regulated by adiponectin treatment. Moreover, the effects of adiponectin on mitochondrial activities and on protection against endotoxin-induced liver injuries were significantly attenuated in UCP2 knockout mice. CONCLUSION: These results suggest that the hepatoprotective properties of adiponectin are mediated at least in part by an enhancement of the activities of MRC complexes through a mechanism involving UCP2.
Hepatology 07/2008; 48(4):1087-96. · 11.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The purpose of this study was to examine the effects of PPAR-gamma agonist rosiglitazone, relative to sulfonylureas, on circulating levels of adiponectin and the prothrombotic factor, plasminogen activator inhibitor (PAI)-1, in type 2 diabetic patients, and to investigate, in animal models, whether the antithrombotic action of rosiglitazone was mediated through adiponectin.
Our clinical study (n=64) showed that after 24-week add-on therapy, the rosiglitazone group had a greater mean reduction in plasma PAI-1 levels (25%, versus 12% in sulfonylurea group, P=0.002). Stepwise multiple linear regression analysis identified the reduction in plasma fasting glucose and the rise in adiponectin levels to be independently associated with the reduction in PAI-I concentration in the rosiglitazone-treated patients. Rosiglitazone (20 mg/kg/d) reduced adipose tissue PAI-1 mRNA expression and its plasma levels in wild-type C57 mice with diet-induced obesity (P<0.001), but this suppressive effect was attenuated in adiponectin knockout mice. Adenovirus-mediated overexpression of adiponectin led to a significant suppression of adipose tissue PAI-1 expression and its circulating concentrations in db/db diabetic mice. Our in vitro study demonstrated that recombinant adiponectin directly inhibited PAI-1 production in 3T3-L1 adipocytes.
The antithrombotic effect of rosiglitazone is mediated, at least in part, through the suppressive effect of adiponectin on PAI-1 production.
Arteriosclerosis Thrombosis and Vascular Biology 12/2007; 27(12):2777-82. · 6.37 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Adiponectin is a multifunctional adipokine that circulates as several oligomeric complexes in the blood stream. However, the molecular basis that regulates the production of the adiponectin oligomers remains largely elusive. We have shown previously that several conserved lysine residues (positions 68, 71, 80, and 104) within the collagenous domain of adiponectin are modified by hydroxylation and glycosylation (Wang, Y., Xu, A., Knight, C., Xu, L. Y., and Cooper, G. J. (2002) J. Biol. Chem. 277, 19521-19529). Here, we investigated the potential roles of these post-translational modifications in oligomeric complex formation of adiponectin. Gel filtration chromatography revealed that adiponectin produced from mammalian cells formed trimeric, hexameric, and high molecular weight (HMW) oligomeric complexes. These three oligomeric forms were differentially glycosylated, with the HMW oligomer having the highest carbohydrate content. Disruption of hydroxylation and glycosylation by substitution of the four conserved lysines with arginines selectively abrogated the intracellular assembly of the HMW oligomers in vitro as well as in vivo. In type 2 diabetic patients, both the ratios of HMW to total adiponectin and the degree of adiponectin glycosylation were significantly decreased compared with healthy controls. Functional studies of adiponectin-null mice revealed that abrogation of lysine hydroxylation/glycosylation markedly decreased the ability of adiponectin to stimulate phosphorylation of AMP-activated protein kinase in liver tissue. Chronic treatment of db/db diabetic mice with wild-type adiponectin alleviated hyperglycemia, hypertriglyceridemia, hepatic steatosis, and insulin resistance, whereas full-length adiponectin without proper post-translational modifications and HMW oligomers showed substantially decreased activities. Taken together, these data suggest that hydroxylation and glycosylation of the lysine residues within the collagenous domain of adiponectin are critically involved in regulating the formation of its HMW oligomeric complex and consequently contribute to the insulin-sensitizing activity of adiponectin in hepatocytes.
Journal of Biological Chemistry 07/2006; 281(24):16391-400. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Approximately one half to two thirds of newly synthesized apolipoprotein B (apoB) in Hep G2 cells (a human hepatoma cell line) is degraded. The intracellular degradation of apoB associated with the rough endoplasmic reticulum (ER) is reviewed in the context of our current understanding of proteasome-mediated degradation of ER-associated proteins. A model of hepatic apoB biogenesis is presented.
Trends in Cardiovascular Medicine.
-
[show abstract]
[hide abstract]
ABSTRACT: APOBEC-1, which mediates the editing of apolipoprotein (apo) B mRNA, is the only known member of the C (cytidine)→U (uridine) editing enzyme subfamily of the cytidine deaminase supergene family. Here we report the cloning of APOBEC-2, another member of the subfamily. Human and mouse APOBEC-2 both contain 224 amino acid residues, and their genes are mapped to syntenic regions of human chromosome 6 (6p21) and mouse chromosome 17. By phylogenetic analysis, APOBEC-2 is shown to be evolutionarily related to APOBEC-1, and analysis of substitution rates indicates that APOBEC-2 is a much better conserved gene than APOBEC-1. APOBEC-2 mRNA and protein are expressed exclusively in heart and skeletal muscle. APOBEC-2 does not display detectable apoB mRNA editing activity. Like other editing enzymes of the cytidine deaminase superfamily, APOBEC-2 has low, but definite, intrinsic cytidine deaminase activity. The identification of APOBEC-2 indicates that APOBEC-1 is not the only member of the C→U editing enzyme subfamily, which, like the A (adenosine)→I (inosine) subfamily of editing enzymes, must encompass at least two and possibly more different deaminase enzymes. It suggests that the C→U editing affecting apoB mRNA and other RNAs is not an isolated event mediated by a single enzyme but involves multiple related proteins that have evolved from a primordial gene closely related to the housekeeping enzyme cytidine deaminase.
Biochemical and Biophysical Research Communications.
