Obesity is associated with nonalcoholic fatty liver disease (NAFLD), which represents a spectrum of liver abnormalities that are characterized by an increase in intrahepatic triacylglycerol (TAG) content (i.e., steatosis) with or without infl ammation and fi brosis (i.e., steatohepatitis). The presence of steatosis is an important marker of metabolic dysfunction and correlates closely with multiorgan insulin resistance and dyslipidemia ( 1 ), which are key risk factors for diabetes and coronary artery disease. However, the mechanisms responsible for the link between increased intrahepatic TAG content and metabolic disease are not clear.It has been hypothesized that the hepatocellular accumulation of specifi c lipid intermediates, including diacylglycerol (DAG), acyl-CoA, and ceramide, in people with NAFLD is the molecular mechanism driving insulin resistance ( 2, 3 ). Accordingly, an understanding of the metabolic interrelationships among hepatic glycerolipid synthesis and lipid intermediates has important physiological and clinical implications. There are two pathways for diacylglycerol synthesis. In the liver, most DAG and TAG are synthesized from the sequential acylation of glycerol-3-phosphate. However, these lipids can also be synthesized from monoacylglycerol through the monoacylglycerol acyltransferase (MGAT) pathway ( Fig. 1 ) ( 4, 5 ). The MGAT and glycerol-3-phosphate pathways are convergent and each results in the synthesis of DAG, which is then acylated to form TAG by the DAG acyltransferase (DGAT) enzymes ( Fig. 1 ). The MGAT pathway is an important TAG Abstract Intrahepatic lipid accumulation is extremely common in obese subjects and is associated with the development of insulin resistance and diabetes. Hepatic diacylglycerol and triacylglycerol synthesis predominantly occurs through acylation of glycerol-3-phosphate. However, an alternative pathway for synthesizing diacylglycerol from monoacylglycerol acyltransferases (MGAT) could also contribute to hepatic glyceride pools. MGAT activity and the expression of the three genes encoding MGAT enzymes ( MOGAT1 , MOGAT2 , and MOGAT3 ) were determined in liver biopsies from obese human subjects before and after gastric bypass surgery. MOGAT expression was also assessed in liver of subjects with nonalcoholic fatty liver disease (NAFLD) or control livers. All MOGAT genes were expressed in liver, and hepatic MGAT activity was readily detectable in liver lysates. The hepatic expression of MOGAT3 was highly correlated with MGAT activity, whereas MOGAT1 and MOGAT2 expression was not, and knockdown of MOGAT3 expression attenuated MGAT activity in a liver-derived cell line. Marked weight loss following gastric bypass surgery was associated with a signifi cant reduction in MOGAT2 and MOGAT3 expression, which were also overexpressed in NAFLD subjects. These data suggest that the MGAT pathway is active and dynamically regulated in human liver and could be an important target for pharmacologic intervention for the treatment of obesity-related insulin resistance and ...

The medicinal chemistry and preclinical biology of imidazopyridine-based inhibitors of diacylglycerol acyltransferase 2 (DGAT2) is described. A screening hit 1 with low lipophilic efficiency (LipE) was optimized through two key structural modifications: (1) identification of the pyrrolidine amide group for a significant LipE improvement, and (2) insertion of a sp(3)-hybridized carbon center in the core of the molecule for simultaneous improvement of N-glucuronidation metabolic liability and off-target pharmacology. The preclinical candidate 9 (PF-06424439) demonstrated excellent ADMET properties and decreased circulating and hepatic lipids when orally administered to dyslipidemic rodent models.

Phone: þ82 10 8717 0978, Fax: þ82 2 958 5229 Transparent double-layer heaters that consist of aluminumdoped zinc oxide and fluorine-doped tin oxide films are prepared by electron cyclotron resonance-metal organic chemical vapor deposition and RF-sputtering systems, in sequence. The double-layered transparent conducting oxide film is designed and prepared to achieve both of high conductivity and high-temperature performance. This double-layer structure has lower sheet resistance, due to the grain size increase with respect to the single-layer films. The fluorine-doped tin oxide/aluminum-doped zinc oxide double-layer film shows a sheet resistance as low as 36.7 V sq À1 , and an optical transmittance of $82%, which are suitable properties for low-voltage transparent heaters. Hall measurement results show that the double-layer film has remarkably increased conductivity and decreased resistivity. In addition, the time-versus-temperature profile shows that the performance of the fluorine-doped tin oxide/aluminumdoped zinc oxide double layer is superior to that of the aluminum-doped zinc oxide and fluorine-doped tin oxide single-layer films.

Ammonia (NH3) is conventionally produced using fossil natural gas (NG) for hydrogen production through steam reformation, and synthesis in Haber-Bosch (HB) process. Conventional ammonia global production contributes to more than...

Inhibition of triacylglycerol (TAG) biosynthetic enzymes has been suggested as a promising strategy to treat insulin resistance, diabetes, dyslipidemia, and hepatic steatosis. Monoacylglycerol acyltransferase 3 (MGAT3) is an integral membrane enzyme that catalyzes the acylation of both monoacylglycerol (MAG) and diacylglycerol (DAG) to generate DAG and TAG, respectively. Herein, we report the discovery and characterization of the first selective small molecule inhibitors of MGAT3. Isoindoline-5-sulfonamide (6f, PF-06471553) selectively inhibits MGAT3 with high in vitro potency and cell efficacy. Because the gene encoding MGAT3 (MOGAT3) is found only in higher mammals and humans, but not in rodents, a transgenic mouse model expressing the complete human MOGAT3 was used to characterize the effects of 6f in vivo. In the presence of a combination of diacylglycerol acyltransferases 1 and 2 (DGAT1 and DGAT2) inhibitors, an oral administration of 6f exhibited inhibition of the incorporation of deuterium-labeled glycerol into TAG in this mouse model. The availability of a potent and selective chemical tool and a humanized mouse model described in this report should facilitate further dissection of the physiological function of MGAT3 and its role in lipid homeostasis.