The most rapidly expanding area in gastrointestinal surgery is bariatric surgery and the continuing epidemic in obesity and related
type 2 diabetes is likely to ensure that this area will grow further in the future. “
“The protein, thyroid hormone-responsive SPOT 14 homolog (Thrsp), has been reported to be a lipogenic gene in cultured hepatocytes, implicating an important role of Thrsp in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Thrsp expression is known to be regulated by a variety of transcription learn more factors, including thyroid hormone receptor, pregnane X receptor, and constitutive androstane receptor. Emerging in vitro evidence also points to a critical role of liver X receptor (LXR) in regulating Thrsp transcription in hepatocytes. In the present study, we showed that Thrsp was up-regulated in livers of db/db mice and high-fat-diet–fed mice, two models of murine NAFLD. Hepatic overexpression of Thrsp increased triglyceride accumulation with enhanced lipogenesis in livers of C57Bl/6 mice, whereas hepatic Thrsp gene silencing attenuated the fatty liver phenotype in db/db mice. LXR activator TO901317 induced Thrsp expression in livers of wild-type (WT) and LXR-β gene-deficient mice, but not in LXR-α or LXR-α/β double-knockout mice. TO901317 treatment significantly enhanced hepatic sterol regulatory element-binding
protein 1c (SREBP-1c) expression and activity in WT mice, but failed to induce Thrsp expression in SREBP-1c gene-deficient mice. Sequence analysis revealed four LXR response-element–like elements and one sterol regulatory nearly element (SRE)-binding Sotrastaurin clinical trial site within a −2,468 ∼+1-base-pair region of the Thrsp promoter. TO901317 treatment and LXR-α overexpression failed to induce, whereas overexpression of SREBP-1c significantly increased Thrsp promoter activity. Moreover, deletion of the SRE site completely abolished SREBP-1c–induced
Thrsp transcription. Conclusion: Thrsp is a lipogenic gene in the liver that is induced by the LXR agonist through an LXR-α–mediated, SREBP-1c–dependent mechanism. Therefore, Thrsp may represent a potential therapeutic target for the treatment of NAFLD. (Hepatology 2013;58:617–628) Nonalcoholic fatty liver disease (NAFLD) is a common component of metabolic syndrome, which has become an epidemic worldwide as a result of improved living conditions, excessive food intake, and sedentary lifestyles. NAFLD comprises a spectrum of liver pathology, including bland steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. NAFLD is estimated to be present in up to 20% of the general population in the United States and ∼15% in China.[1] NAFLD is mostly accompanied by obesity, type 2 diabetes, and dyslipidemia.[2] Although the underlying mechanisms remain unclear, NAFLD is considered to represent a state of fat accumulation, mainly triglycerides (TGs), in hepatocytes, and its pathogenesis is associated with hepatic insulin resistance and enhanced liver lipogenesis.