Publications (3)13.97 Total impact
Article: Halofenate is a selective peroxisome proliferator-activated receptor gamma modulator with antidiabetic activity.[show abstract] [hide abstract]
ABSTRACT: Halofenate has been shown previously to lower triglycerides in dyslipidemic subjects. In addition, significant decreases in fasting plasma glucose were observed but only in type 2 diabetic patients. We hypothesized that halofenate might be an insulin sensitizer, and we present data to suggest that halofenate is a selective peroxisome proliferator-activated receptor (PPAR)-gamma modulator (SPPARgammaM). We demonstrate that the circulating form of halofenate, halofenic acid (HA), binds to and selectively modulates PPAR-gamma. Reporter assays show that HA is a partial PPAR-gamma agonist, which can antagonize the activity of the full agonist rosiglitazone. The data suggest that the partial agonism of HA may be explained in part by effective displacement of corepressors (N-CoR and SMRT) coupled with inefficient recruitment of coactivators (p300, CBP, and TRAP 220). In human preadipocytes, HA displays weak adipogenic activity and antagonizes rosiglitazone-mediated adipogenic differentiation. Moreover, in 3T3-L1 adipocytes, HA selectively modulates the expression of multiple PPAR-gamma-responsive genes. Studies in the diabetic ob/ob mouse demonstrate halofenate's acute antidiabetic properties. Longer-term studies in the obese Zucker (fa/fa) rat demonstrate halofenate's comparable insulin sensitization to rosiglitazone in the absence of body weight increases. Our data establish halofenate as a novel SPPARgammaM with promising therapeutic utility with the potential for less weight gain.Diabetes 10/2006; 55(9):2523-33. · 8.29 Impact Factor
Article: Novel PEX1 mutations and genotype-phenotype correlations in Australasian peroxisome biogenesis disorder patients.[show abstract] [hide abstract]
ABSTRACT: The peroxisome biogenesis disorders (PBDs) are a group of neuronal migration/neurodegenerative disorders that arise from defects in PEX genes. A major subgroup of the PBDs includes Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD). These three disorders represent a clinical continuum with Zellweger syndrome the most severe. Mutations in the PEX1 gene, which encodes a protein of the AAA ATPase family involved in peroxisome matrix protein import, account for the genetic defect in more than half of the patients in this PBD subgroup. We report here on the results of PEX1 mutation detection in an Australasian cohort of PEX1-deficient PBD patients. This screen has identified five novel mutations, including nonsense mutations in exons 14 and 19 and single nucleotide deletions in exons 5 and 18. Significantly, the allele carrying the exon 18 frameshift mutation is present at moderately high frequency (approx. 10%) in this patient cohort. The fifth mutation is a missense mutation (R798G) that attenuates, but does not abolish PEX1 function. We have evaluated the cellular impact of these novel mutations, along with that of the two most common PEX1 mutations (c.2097-2098insT and G843D), in PBD patients by determining the levels of PEX1 mRNA, PEX1 protein, and peroxisome protein import. The findings are consistent with a close correlation between cellular phenotype, disease severity, and PEX1 genotype.Human Mutation 12/2002; 20(5):342-51. · 5.69 Impact Factor
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ABSTRACT: Recent decades have seen a worldwide explosion of obesity and type 2 diabetes. Type 2 diabetes accounts for 85-90% of all diabetes cases with an estimated 940,000 Australians aged 25 years and over afflicted. This number has trebled since 1981. Globally, type 2 diabetes afflicts approximately 150-200 million people, with this number expected to increase to 300 million by 2010. A major contributor to this massive increase in type 2 diabetes is obesity. World wide, more than 1 billion adults are overweight with at least 300 million of these clinically obese. This rapid rise in lifestyle related diseases reflects changes in behavioural patterns including diets consisting of high proportions of saturated fats and sugar and a tendency toward less physical activity. This trend is proving to socially and economically burden communities worldwide. Current therapies for the treatment of type 2 diabetes include a class of glucose lowering, insulin sensitising drugs, thiazolidinediones (TZDs), which were developed before the molecular target had been identified. Research has since identified the nuclear receptor Peroxisome Proliferator-Activated Receptor y (PPARy) as the molecular target of these drugs. Activation of this receptor by TZDs has been found to ameliorate the metabolic disturbances associated with type 2 diabetes ie hyperglycemia, hyperinsulinemia, insulin resistance and some aspects of dyslipidemia. Unfortunately, the current therapies that target PPARy produce adverse side effects, particularly in those patients co-treated with insulin, including edema and weight gain, which are counterproductive in the context of the metabolic syndrome. As a result, there is a requirement for the identification of novel compounds that can elicit the positive antidiabetic effects while avoiding negative side effects. Such compounds include SPPARyMs (Selective PPARy Modulators). These compounds are partial agonists/antagonists of PPARy, capable of differentially modulating cofactor interaction and resultant gene expression relative to full agonists. In addition, they are capable of antagonising the PPARy mediated effects elicited by full agonists in a cell specific manner. We demonstrate that halofenate, a phenoxy acetic acid derivative, initially described and utilised in the 1970s to lower triglycerides and glucose in type 2 diabetic patients, is a SPPARyM. Halofenic acid, the circulating form of halofenate, binds to and modulates PPARy. It is a partial agonist that is capable of antagonising the activity of the full agonist, rosiglitazone. It displays weak adipogenic potential and antagonises rosiglitazone-mediated adipogenic differentiation in human preadipocytes. In 3T3-L1 adipocytes, halofenic acid differentially modulates the expression of PPARy target genes. This partial agonism/antagonism may be explained in part by the attenuated displacement of corepressors (N-CoR and SMRT) coupled with the defective recruitment of coactivators (p300, CBP and TRAP220). In vivo studies in ob/ob and fa/fa rodents demonstrate that halofenate is equally as efficacious as rosiglitazone at ameliorating insulin resistance, but without eliciting weight gain. Second generation halofenate derivatives were also found to differentially activate PPARy and PPARa. These compounds are partial PPARy agonists, capable of dose dependently activating PPARy with reduced efficacy and/or potency compared to rosiglitazone. Each compound also displays a unique efficiency and potency at displacing corepressors and recruiting coactivators. On the basis of these findings the halofenate derivatives were similarly classified as SPPARyMs. The modulation of PPARy activity and interactions with cofactors by SPPARyMs ultimately leads to a distinct gene expression profile. Analysis of target genes in C2C12 skeletal muscle cells reveal these compounds have differential effects on the expression of genes involved in lipid and glucose metabolism, in comparison to rosiglitazone. It is these discrete changes in the down stream effects of PPARy signalling that may lead to a more beneficial metabolic outcome than that observed for full PPARy agonists. Despite the differences in the modulation of PPARy activities, halofenate and its derivatives have been found to retain the insulin sensitising effects of full agonists while avoiding the side effects associated with them. These compounds may provide not only a novel approach to treating type 2 diabetes, but also offer a unique tool in further understanding PPARy signalling and its role in ameliorating symptoms associated with insulin resistance and type 2 diabetes.