The impact of bariatric surgery on nonalcoholic fatty liver disease as measured using non-invasive tests.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is common in bariatric surgery candidates. We evaluated the effect of sleeve gastrectomy (SG) on NAFLD using validated non-invasive measures. METHODS: Patients with morbid obesity and NAFLD, planned for SG, were evaluated before and after surgery. Data collected included anthropometrics, biochemistry, adiponectin, SteatoTest™, NashTest™, FibroTest™, OWLiver® test and real-time ShearWave™ elastography (SWE). RESULTS: Twenty-six subjects were included in the study, mean age 44.1 ± 4.8 years, 69.2% males. One year following SG, body mass index decreased significantly from 41.7 ± 4.8 kg/m2 to 29.6 ± 4.5 kg/m2. Concomitantly, significant improvements in triglycerides, ALT, diabetes markers and adiponectin were observed. Mean steatosis, as measured by SteatoTest™, was significantly improved. Steatohepatitis score measured by NashTest™ and OWLiver® significantly decreased. Mean fibrosis, as measured by SWE liver stiffness and FibroTest™, did not change over time. CONCLUSION: Steatosis and steatohepatitis are significantly improved by SG as measured by non-invasive measures.

Both MAPK and STAT3 signal transduction pathways are necessary for IL-6-dependent hepatic stellate cells activation.

BACKGROUND: During liver injury, hepatic stellate cells (HSCs) can undergo activation and transform into alpha-smooth muscle actin (αSMA)-expressing contractile myofibroblast-like cells, leading to deposition of excessive scar matrix. We have recently demonstrated that depletion of adenosine deaminase acting on double-stranded RNA (ADAR1) from mouse hepatocytes leads to HSC activation and induction of inflammation and hepatic fibrosis that is mediated by interleukin 6 (IL-6). Our aim was to identify and characterize the molecular pathways involved in the direct, inflammation-independent activation of HSCs by IL-6. METHODS: Primary HSCs were isolated from mouse livers. mRNA levels of αSMA and Col1a were analyzed using qRT-PCR. Protein levels of αSMA, MAPK, p-MAPK, p38, p-p38, STAT3 and p-STAT3 were assessed by Western Blot analysis. The effect of specific signal transduction pathway inhibitors (i.e., SB203580 (P-38 inhibitor), U0126 (MAPK inhibitor), S3I-201 (STAT3 inhibitor) and Ruxolitinib (Jak1/2 inhibitor)) was also studied. RESULTS: Primary HSCs treated with IL-6 demonstrated upregulation of αSMA and Col1a mRNA levels as well as increased αSMA protein levels. Moreover, the phenotypic transition of quiescent HSCs toward myofibroblast-like cells was noted upon administration of IL-6 and not in untreated samples. In addition, the phosphorylation levels of p38, MAPK and STAT3 increased 30 minutes after treatment, and was followed by a decline in the phosphorylation levels 2-4 hours post-treatment. However, addition of specific signal transduction pathway inhibitors curbed this effect, and resulted in αSMA and Col1a expression levels similar to those measured in untreated control samples. CONCLUSION: IL-6 can directly induce the transition of HSCs toward myofibroblast-like cells. The effect is mediated by the activation of both MAPK and JAK/STAT signaling pathways. Elimination of either MAPK or JAK/STAT signaling pathways inhibits HSC stimulation. These results might pave the road toward the development of potential therapeutic interventions for hepatic fibrosis.