Furthermore,

in vivo RBP4 infusion induced SREBP-1c activation and consequently accelerated hepatic lipogenesis and plasma TAG in C57BL/6J mice, a phenomenon not observed in Ppargc1b knockout mice. Conclusion: These findings reveal a novel mechanism by which Selleck PD332991 RBP4 achieves its effects on hepatic lipid metabolism. (HEPATOLOGY 2013;8:564-575) Retinol binding protein 4 (RBP4), a protein that belongs to the lipocalin family, was initially known as a specific carrier for the delivery of retinol (vitamin A) in the circulation.[1, 2] It is encoded by the RBP4 gene, localized in chromosome 10q23-q24.[3] Hepatocytes are regarded as the major source of RBP4 secretion under normal conditions[4]; however, adipose tissue expresses a considerable amount of RBP4[5] and could make a substantial contribution to elevated serum RBP4 levels in insulin-resistant states.[6] RBP4 is identified as a new adipokine suggested to link obesity with its comorbidities, especially insulin resistance, type 2 diabetes (T2D), and certain components of the metabolic syndrome. Serum RBP4 concentrations are elevated in subjects with impaired glucose tolerance, T2D, and correlate inversely with insulin sensitivity in nondiabetic subjects with a family history of T2D.[7] Circulating NVP-BKM120 RBP4 levels correlate with the degree of insulin resistance in these subjects and the relationship

is independent of obesity.[8] Transgenic overexpression of human RBP4 or injection of recombinant RBP4 in normal mice induced 上海皓元医药股份有限公司 insulin resistance.[10] Conversely, heterozygous or homozygous RBP4 knockout mice had improved insulin sensitivity.[10] Increased serum RBP4 decreased glucose transporter type 4 (Glut4)

expression in adipocytes and induced expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) in hepatocytes, thus contributing to the impairment of systemic insulin resistance.[10] Recently, a high circulating level of RBP4 was demonstrated to associate with elevated liver fat accumulation in human studies.[11] Blocking RBP4 expression in the liver was sufficient to reduce lipid droplets and ameliorate high fat diet-induced hepatic steatosis in C57BL/6 mice, which confirmed the potential role of RBP4 in the regulation of lipid metabolism in liver.[14] However, the pathophysiological roles of RBP4 involved in the regulation of hepatic lipid metabolism and the underlying molecular mechanism has not yet been fully characterized. Sterol regulatory element binding protein (SREBP) is known as a key lipogenic transcription factor controlling the biosynthesis of cholesterol, fatty acids, and triglyceride (TAG).[15, 16] Mammalian genomes have two separate SREBP genes (SREBF1 and SREBF2). SREBP-1 expression produces two different isoforms, SREBP-1a and -1c.