Association of Hepatic Steatosis Index with Nonalcoholic Fatty Liver Disease Diagnosed by Non-Enhanced CT in a Screening Population.

The noninvasive diagnosis of hepatic steatosis is of increasing concern. This study investigated the association of hepatic steatosis determined by non-enhanced CT criteria with clinical parameters in a screening population. Asymptomatic patients who underwent abdominal CT at our healthcare center were retrospectively analyzed (n = 339). Two radiologists measured the attenuation values of the liver parenchyma and spleen using non-enhanced CT images. CT criteria for hepatic steatosis were (a) absolute liver attenuation value <48 Hounsfield units (HU), (b) liver-to-spleen attenuation ratio <0.8, and (c) attenuation difference between the liver and spleen <-10. Body mass index (BMI) and hepatic steatosis index (HSI) were calculated, and laboratory findings were recorded. The association of hepatic steatosis with clinical parameters was assessed using univariate and logistic regression analyses. The presence of hepatic steatosis was significantly associated with the levels of serum fasting glucose and triglycerides, the alanine aminotransferase to aspartate aminotransferase (ALT/AST) ratio, BMI, and HSI values using any of the CT criteria. Logistic regression analysis revealed that the serum fasting glucose level and HSI were significantly associated with hepatic steatosis using criterion (a), while the ALT/AST ratio and HSI were associated with hepatic steatosis using criteria (b) and (c). The presence of hepatic steatosis on non-enhanced CT should be considered to indicate possible clinical profile abnormalities regarding metabolic syndrome.

Hypoxia inhibits adipocyte differentiation in a HDAC-independent manner.

Oxygen is the most important factor for the appropriate regulation of multiple energy homeostasis and cell differentiation. Although hypoxia-induced signaling cascades have been intensively studied, the molecular mechanism by which hypoxic signals suppress adipocyte differentiation is unclear. Here, we demonstrated that repression of adipocyte differentiation by hypoxia and HIF1alpha- or Stra13-overexpression was not associated with HDACs. Furthermore, HDACs did not affect inhibitory effect of Stra13 on PPARgamma promoter activity, although the hypoxia-induced suppression of adipogenesis was accompanied with reduced acetylation of histone H3 and H4 at the PPARgamma promoter. Instead, we revealed that hypoxic circumstances biphasically activated AMPK and concomitantly blocked clonal expansion of preadipocytes, which is an indispensable step for early phase of adipocyte differentiation. Taken together, these results suggest that hypoxic condition attenuates adipocyte differentiation by inhibition of PPARgamma expression in a HDAC-independent manner and by activation of AMPK which impairs clonal expansion phase.

Insulin and hypoxia share common target genes but not the hypoxia-inducible factor-1alpha.

Both hypoxia and insulin induce common target genes, including vascular endothelial growth factors and several glycolytic enzymes. However, these two signals eventually trigger quite different metabolic pathways. Hypoxia induces glycolysis, resulting in anaerobic ATP production, while insulin increases glycolysis for energy storage. Hypoxia-induced gene expression is mediated by the hypoxia-inducible factor-1 (HIF-1) that consists of HIF-1alpha and the aromatic hydrocarbon nuclear translocator (Arnt). Hypoxia-induced gene expression is initiated by the stabilization of the HIF-1alpha subunit. Here we investigated whether insulin-induced gene expression also requires stabilization of HIF-1alpha. Our results indicate that hypoxia but not insulin stabilizes HIF-1alpha protein levels, whereas both insulin- and hypoxia-induced gene expression require the presence of the Arnt protein. Insulin treatment fails to inactivate proline hydroxylation of HIF-1alpha, which triggers recruitment of the von Hippel-Lindau protein and oxygen-dependent degradation of HIF-1alpha. Insulin-induced gene expression is inhibited by the presence of the phosphoinositide (PI) 3-kinase inhibitor LY294002 and the dominant negative mutant of the p85 subunit of PI 3-kinase, whereas hypoxia-induced gene expression is not. Pyrrolidine dithiocarbamate, a scavenger of H2O2, reduces insulin-induced gene expression but not hypoxia-induced gene expression. Although both hypoxia and insulin induce the expression of common target genes through a hypoxia-responsive element- and Arnt-dependent mechanism, insulin cannot stabilize the HIF-1alpha protein. We believe that insulin activates other putative partner proteins for Arnt in PI 3-kinase- and H2O2-dependent pathways.