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Obesity and insulin resistance are primary risk factors for Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD is generally exhibited by non-progressive simple steatosis. However, a significant subset of patient’s progress to nonalcoholic steatohepatitis (NASH) that is defined by the presence of steatosis, inflammation and hepatocyte injury with fibrosis. Unfortunately, there are no approved therapies for NAFLD or NASH and therefore therapeutic approaches are urgently needed. Niclosamide is an U.S. Food and Drug Administration (FDA)-approved anthelmintic drug that mediates its effect by uncoupling oxidative phosphorylation. Niclosamide and its salt forms, Niclosamide Ethanolamine (NEN), and Niclosamide Piperazine (NPP) have shown efficacy in murine models of diet induced obesity characterized by attenuation of the prominent fatty liver disease phenotype and improved glucose metabolism. While the exact mechanism(s) underlying these changes remains unclear, the ability to uncouple oxidative phosphorylation leading to increased energy expenditure and lipid metabolism or attenuation of PKA mediated glucagon signaling in the liver have been proposed. Unfortunately, niclosamide has very poor water solubility, leading to low oral bioavailability. This, in addition to mitochondrial uncoupling activity and potential genotoxicity have reduced enthusiasm for its clinical use. More recently, salt forms of niclosamide, NEN and NPP, have demonstrated improved oral bioavailability while retaining activity. This suggests that development of safer more effective niclosamide derivatives for the treatment of NAFLD and Type 2 Diabetes may be possible. Herein we explored the ability of a series of N-substituted phenylbenzamide derivatives of the niclosamide salicylanilide chemotype to attenuate hepatic steatosis using a novel phenotypic in vitro model of fatty liver and the high fat diet-fed mouse model of diet induced obesity. These studies identified novel compounds with improved pre-clinical properties that attenuate hepatic steatosis in vitro and in vivo. These compounds with improved drug properties may be useful in alleviating symptoms and protection against disease progression in patients with metabolic syndrome and NAFLD. [ABSTRACT FROM AUTHOR]

Carbonic anhydrases are a family of enzymes that catalyze the reversible condensation of water and carbon dioxide to carbonic acid, which spontaneously dissociates to bicarbonate. Carbonic anhydrase III (Car3) is nutritionally regulated at both the mRNA and protein level. It is highly enriched in tissues that synthesize and/or store fat: liver, white adipose tissue, brown adipose tissue, and skeletal muscle. Previous characterization of Car3 knockout mice focused on mice fed standard diets, not high-fat diets that significantly alter the tissues that highly express Car3. We observed lower protein levels of Car3 in high-fat diet fed mice treated with niclosamide, a drug published to improve fatty liver symptoms in mice. However, it is unknown if Car3 is simply a biomarker reflecting lipid accumulation or whether it has a functional role in regulating lipid metabolism. We focused our in vitro studies toward metabolic pathways that require bicarbonate. To further determine the role of Car3 in metabolism, we measured de novo fatty acid synthesis with in vitro radiolabeled experiments and examined metabolic biomarkers in Car3 knockout and wild type mice fed high-fat diet. Specifically, we analyzed body weight, body composition, metabolic rate, insulin resistance, serum and tissue triglycerides. Our results indicate that Car3 is not required for de novo lipogenesis, and Car3 knockout mice fed high-fat diet do not have significant differences in responses to various diets to wild type mice. [ABSTRACT FROM AUTHOR]