Hepatic AdipoR2 signaling plays a protective role against progression of nonalcoholic steatohepatitis in mice.

UNLABELLED: It is unclear how hepatic adiponectin resistance and sensitivity mediated by the adiponectin receptor, AdipoR2, contributes to the progression of nonalcoholic steatohepatitis (NASH). The aim of this study was to examine the roles of hepatic AdipoR2 in NASH, using an animal model. We fed C57BL/6 mice a methionine-deficient and choline-deficient (MCD) diet for up to 8 weeks and analyzed changes in liver pathology caused by either an AdipoR2 short hairpin RNA-expressing adenovirus or an AdipoR2-overexpressing adenovirus. Inhibition of hepatic AdipoR2 expression aggravated the pathological state of NASH at all stages: fatty changes, inflammation, and fibrosis. In contrast, enhancement of AdipoR2 expression in the liver improved NASH at every stage, from the early stage to the progression of fibrosis. Inhibition of AdipoR2 signaling in the liver diminished hepatic peroxisome proliferator activated receptor (PPAR)-alpha signaling, with decreased expression of acyl-CoA oxidase (ACO) and catalase, leading to an increase in lipid peroxidation. Hepatic AdipoR2 overexpression had the opposite effect. Reactive oxygen species (ROS) accumulation in liver increases hepatic production of transforming growth factor (TGF)-beta1 at all stages of NASH; adiponectin/AdipoR2 signaling ameliorated TGF-beta-induced ROS accumulation in primary cultured hepatocytes, by enhancing PPAR-alpha activity and catalase expression. CONCLUSION: The adiponectin resistance and sensitivity mediated by AdipoR2 in hepatocytes regulated steatohepatitis progression by changing PPAR-alpha activity and ROS accumulation, a process in which TGF-beta signaling is implicated. Thus, the liver AdipoR2 signaling pathway could be a promising target in treating NASH.

Utility of quantitative 99mTc-phytate scintigraphy to diagnose early-stage non-alcoholic steatohepatitis.

OBJECTIVE: In patients with non-alcoholic fatty liver disease (NAFLD), liver biopsy remains the only reliable method to differentiate simple steatosis from non-alcoholic steatohepatitis (NASH). The objective of this study was to evaluate the efficacy of non-invasive (99m)Tc-phytate scintigraphy in the diagnosis of NASH. MATERIAL AND METHODS: Thirty-seven patients with suspected NAFLD at the time of liver biopsy also underwent (99m)Tc-phytate scintigraphy. Signal intensities of regions of interest (ROI) in the liver, spleen, and heart were measured. We also examined scintigraphic features in a nutritional model of NASH in rats fed a methionine- and choline-deficient (MCD) diet. RESULTS: The liver/spleen uptake ratio determined by scintigraphy was significantly decreased in patients with NASH in comparison with patients with simple steatosis. The liver/spleen ratio was an independent predictor distinguishing NASH from simple steatosis. The decrease was observed for all stages of NASH, including the early stage (stages 1 and 0). In animal studies, the liver/spleen uptake ratio was significantly decreased in rats after 8 weeks of MCD dietary feeding in comparison with control diet-fed rats. CONCLUSIONS: The non-invasive (99m)Tc-phytate scintigraphy test is a reliable tool to differentiate NASH from simple steatosis.

Evaluating the severity of nonalcoholic steatohepatitis with superparamagnetic iron oxide-enhanced magnetic resonance imaging.

PURPOSE: To evaluate the utility of noninvasive assessment of human nonalcoholic fatty liver disease (NAFLD) patients using superparamagnetic iron oxide (SPIO)-enhanced MRI. MATERIALS AND METHODS: Nineteen NAFLD patients underwent SPIO-enhanced MRI. The values of tau, a time constant for an exponential approximation, were calculated using gradient-echo echo-planar imaging, and the values of %T2, a marker of the T2 relaxation effect of SPIO, were calculated using T2-weighted fast spin-echo images. Correlations between these values and the histological NAFLD activity scores were evaluated. The study protocol was approved by our Institutional Review Board and all patients gave informed consent. RESULTS: There was a statistically significant relationship between the NAFLD activity scores and the tau values (r = 0.66, P = 0.002). The %T2 values were also significantly correlated with the NAFLD activity score (r = -0.58, P = 0.009). A cutoff tau value of 42.8 predicted "definitive NASH" (NAFLD activity score >or=5) with a specificity of 66.7% and a sensitivity of 99.9%, whereas a cutoff %T2 value of 32.5 predicted "definitive NASH" with a specificity of 72.7% and a sensitivity of 87.5%. CONCLUSION: Noninvasive SPIO-enhanced MRI may be helpful for identifying NASH patients among patients suspected of having NAFLD.