Gastroenterology and hepatology news

Pioglitazone Trial for NASH: Results Show Promise

The beneficial effects of rosiglitazone on non-alcoholic fatty liver disease (NAFLD) have been reported. Rosiglitazone treatment stimulates the production of adiponectin, an insulin-sensitizing adipokine with hepatoprotective functions. The present study aims to investigate the hepatic actions of rosiglitazone in mice without adiponectin.

NAFLD was induced in wild type and adiponectin knockout (AKO) mice by high-fat diet feeding. After rosiglitazone treatment, mice were subjected to evaluations on systemic insulin sensitivity, lipid profiles, hepatic steatosis, and inflammation, as well as the expression and activity of key molecules involved in energy metabolism and mitochondrial functions.

Rosiglitazone treatment prevented hepatic inflammation and reduced the expression of pro-inflammatory cytokines in livers of wild type mice. In contrast, in livers of AKO mice, the same treatment induced severe hepatomegaly and microvesicular hepatosteatosis, and caused abnormal accumulation of fatty acyl CoA, glycogen, and their intermediate metabolites. Compared to wild type littermates, the anti-inflammatory and the mitochondria-stimulatory activity of rosiglitazone were largely attenuated in AKO mice. Replenishment with either adiponectin or uncoupling protein 2 (UCP2) significantly reduced fatty acyl CoA accumulation and increased mitochondrial activities in livers of rosiglitazone-treated AKO mice. In addition, adiponectin, but not UCP2, promoted the activation of glycogen synthase kinase 3beta (GSK3beta), a key molecule involved in regulating glycogen homeostasis.

Rosiglitazone elicits its protective functions against NAFLD largely through the induction of adiponectin, which prevents mitochondria stresses by promoting GSK3beta activation and UCP2 upregulation, two pathways coordinating the glucose and lipid metabolism in liver.

Peroxisome proliferator-activated receptor γ (PPARγ) is induced in leptin-deficient (ob/ob) mouse liver and is critical for the development of hepatic steatosis. The present study shows that fat-specific protein 27 (Fsp27) in ob/ob liver is a direct target gene of PPARγ and can elevate hepatic triglyceride levels. FSP27 belongs to the CIDE family, composed of CIDE A, CIDE B, and FSP27/CIDE C, all of which contain a conserved CIDE-N domain. FSP27 was recently reported to be a lipid droplet-binding protein and to promote lipid accumulation in adipocytes. The Fsp27 gene was expressed at high levels in ob/ob liver and at markedly lower levels in ob/ob livers lacking PPARγ. Forced expression of FSP27 by adenovirus in hepatocytes in vitro or in vivo led to increased triglyceride levels. Knockdown by adenovirus expressing FSP27 shRNA resulted in lower accumulation of hepatic triglycerides compared to control adenovirus-infected liver. Taken together, these results indicate that FSP27 is a direct mediator of PPARγ-dependent hepatic steatosis.