t0901317 and Body-Weight

Deoxypodophyllotoxin (DPT) is a naturally occurring flavolignan in Anthriscus sylvestris known as cow parsley or wild chervil, and has been reported to have inhibitory effects against several pathological processes including cancer, inflammation and infection. Here, we report the effects of DPT in the fatty liver induced by high fat diet in vivo as well as its regulatory mechanism related with the transcription factor for lipogenic genes such as sterol regulatory element binding protein-1c (SREBP-1c) in vitro. C57BL/6 mice were fed high fat diet for 10 weeks and also orally administrated with DPT for additional 4 weeks. 5 and 10 mg/kg of DPT decreased lipid accumulation in the liver induced by high fat diet, as indicated by histological parameters such as Oil Red O staining and hematoxylin & eosin as well as the contents of hepatic triglyceride and cholesterol. In hepatocytes, DPT inhibited the liver X receptor α-mediated SREBP-1c induction and expression of the lipogenic genes, including fatty acid synthase, acetyl-CoA carboxylase and stearoyl-CoA desaturase-1. Moreover, DPT induced AMP-activated protein kinase (AMPK) activation, which has been known to inhibit the expression of SREBP-1c in hepatocyte. Also this compound restored the dysregulation of AMPK and SREBP-1c induced by high fat diet in mice. In conclusion, we demonstrated that DPT significantly inhibited fatty liver by adjusting lipid metabolism coordinated with AMPK activation and SREBP-1c inhibition.

Topics: AMP-Activated Protein Kinases; Animals; Apiaceae; Body Weight; Cholesterol; Diet, High-Fat; Drugs, Chinese Herbal; Hep G2 Cells; Humans; Hydrocarbons, Fluorinated; Lipid Metabolism; Liver; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Podophyllotoxin; Signal Transduction; Sterol Regulatory Element Binding Protein 1; Sulfonamides; Triglycerides; Up-Regulation

Liver X receptors (LXRs) are transcription factors known for their role in hepatic cholesterol and lipid metabolism. Though highly expressed in fat, the role of LXR in this tissue is not well characterized. We generated adipose tissue LXRα knockout (ATaKO) mice and showed that these mice gain more weight and fat mass on a high-fat diet compared with wild-type controls. White adipose tissue (WAT) accretion in ATaKO mice results from both a decrease in WAT lipolytic and oxidative capacities. This was demonstrated by decreased expression of the β2- and β3-adrenergic receptors, reduced level of phosphorylated hormone-sensitive lipase, and lower oxygen consumption rates (OCRs) in WAT of ATaKO mice. Furthermore, LXR activation in vivo and in vitro led to decreased adipocyte size in WAT and increased glycerol release from primary adipocytes, respectively, with a concomitant increase in OCR in both models. Our findings show that absence of LXRα in adipose tissue results in elevated adiposity through a decrease in WAT oxidation, secondary to attenuated FA availability.

Topics: Adipocytes, White; Animals; Body Weight; Diet, High-Fat; Fatty Acids; Gene Expression Regulation; Gene Knockout Techniques; Hydrocarbons, Fluorinated; Lipolysis; Liver X Receptors; Male; Mice; Mitochondria; Obesity; Orphan Nuclear Receptors; Oxidation-Reduction; Oxygen Consumption; Phenotype; Receptors, Adrenergic, beta; Sulfonamides

Liver X receptor (LXR) ligands are currently being evaluated as potential therapeutic agents for the treatment of low HDL. The LXR ligand T0901317 elevates ATP binding cassette transporter A1 (ABCA1) and HDL levels in animal models and induces moderate lipogenesis through upregulation of sterol regulatory element binding protein 1c (SREBP1c). Because insulin may also regulate lipogenesis through SREBP1c and fatty acid synthase (FAS), we investigated the effect of an LXR ligand in hyperinsulinemic mice. Administration of T0901317 to male db/db mice for 12 days resulted in a more severe hypertriacylglycerolemia and hepatic triacylglycerol accumulation than observed in nondiabetic mice. The LXR target genes ABCA1, SREBP1c, FAS, and stearoyl-CoA desaturase 1 were upregulated by T0901317 treatment in both diabetic db/db and nondiabetic C57BLKS mice. Changes in lipogenic gene expression were independent of mouse strain, indicating that the severe lipogenesis observed in LXR ligand-treated db/db mice was not due to additive effects of insulin on lipogenic gene expression. Phosphoenolpyruvate carboxykinase expression was suppressed, suggesting that a shift from gluconeogenesis toward lipogenesis could partially explain our observations in db/db mice. Our data suggest that LXR ligands that have effects on both fatty acid and carbohydrate metabolism should be carefully evaluated in obesity, insulin, and leptin resistance.

Topics: Animals; Anticholesteremic Agents; Body Weight; Cholesterol; Diabetes Mellitus; Disease Models, Animal; Hydrocarbons, Fluorinated; Insulin; Ligands; Lipids; Lipoproteins; Liver; Male; Mice; Mice, Transgenic; Organ Size; Receptors, Cytoplasmic and Nuclear; Sulfonamides; Triglycerides