Levels of STING were increased in liver tissues from patients with NAFLD and mice with HFD-induced steatosis. In mice, loss of STING from macrophages decreased the severity of liver fibrosis and the inflammatory response. STING might be a therapeutic target for NAFLD.

BaCKgRoUND aND aIMS: Indole is a microbiota metabolite that exerts anti-inflammatory responses. However, the relevance of indole to human non-alcoholic fatty liver disease (NAFLD) is not clear. It also remains largely unknown whether and how indole acts to protect against NAFLD. The present study sought to examine the association between the circulating levels of indole and liver fat content in human subjects and explore the mechanisms underlying indole actions in mice with diet-induced NAFLD. appRoaCH aND ReSUltS: In a cohort of 137 subjects, the circulating levels of indole were reversely correlated with body mass index. In addition, the circulating levels of indole in obese subjects were significantly lower than those in lean subjects and were accompanied with increased liver fat content. At the whole-animal level, treatment of high-fat diet (HFD)-fed C57BL/6J mice with indole caused significant decreases in the severity of hepatic steatosis and inflammation. In cultured cells, indole treatment stimulated the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a master regulatory gene of glycolysis, and suppressed macrophage proinflammatory activation in a PFKFB3-dependent manner. Moreover, myeloid cell-specific PFKFB3 disruption exacerbated the severity of HFD-induced hepatic steatosis and inflammation and blunted the effect of indole on alleviating diet-induced NAFLD phenotype. CoNClUSIoNS: Taken together, our results demonstrate that indole is relevant to human NAFLD and capable of alleviating diet-induced NAFLD phenotypes in mice in a myeloid cell PFKFB3-dependent manner. Therefore, indole mimetic and/or macrophage-specific PFKFB3 activation may be the viable preventive and/or therapeutic approaches for inflammation-associated diseases including NAFLD. (Hepatology 2020;72:1191-1203). N onalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis and progresses to nonalcoholic steatohepatitis (NASH) when the liver displays overt inflammatory damage. (1,2) As the advanced form of NAFLD, NASH is one of the most common causes of liver

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Taken together, our results demonstrate that disruption of A R in both macrophage and hepatocytes accounts for increased severity of NAFLD, likely through increasing inflammation and through elevating lipogenic events due to stimulation of SREBP1c expression and transcription activity. (Hepatology 2018;68:48-61).

The diagnosis of primary aldosteronism typically requires at least one confirmatory test. The fludrocortisone suppression test is generally accepted as a reliable confirmatory test, but it is cumbersome. Evidence from accuracy studies of the saline infusion test (SIT) and the captopril challenge test (CCT) has provided conflicting results. This prospective study aimed to evaluate the diagnostic accuracy of the SIT and CCT using fludrocortisone suppression test as the reference standard. One hundred thirty-five patients diagnosed with primary aldosteronism and 101 patients diagnosed with essential hypertension who completed the 3 confirmatory tests were included for the diagnostic accuracy analysis. The areas under the receiver-operator characteristics curves of the CCT and SIT were 0.96 (95% confidence interval [CI], 0.92-0.98) and 0.96 (95% CI, 0.92-0.98), respectively, using post-test plasma aldosterone concentration (PAC) for diagnosis. However, the areas under the receiver-operator characteristics curves of the CCT decreased to 0.71 (95% CI, 0.65-0.77) when the PAC suppression percentage was used to diagnose primary aldosteronism. The optimal cutoff of PAC post-CCT was set at 11 ng/dL, resulting in a sensitivity of 0.90 (95% CI, 0.84-0.95) and a specificity of 0.90 (95% CI, 0.83-0.95), which were not significantly different from those of SIT (with PAC post-SIT set at 8 ng/dL, sensitivity: 0.85 [95% CI, 0.78-0.91], =0.192; specificity: 0.92 [95% CI, 0.85-0.97],=0.551). In conclusion, both CCT and SIT are accurate alternatives to the more complex fludrocortisone suppression test. Because CCT is safe and much easier to perform, it may serve as a more feasible alternative. When interpreting the results of CCT, PAC post-CCT is highly recommended.

Context More than half of patients diagnosed with unilateral primary aldosteronism (UPA) suffer from persisting hypertension after unilateral adrenalectomy. Objective To develop and validate a nomogram-based preoperative score (NBPS) to predict clinical outcomes after unilateral adrenalectomy for UPA. Design and setting The NBPS was developed in an Asian cohort by incorporating predictors independently associated with remission of hypertension after unilateral adrenalectomy for UPA and validated in a Caucasian cohort. Participants Patients with UPA achieving complete biochemical success after unilateral adrenalectomy. Main outcome measure the predictive performance of NBPS compared with two previously developed outcome prediction scores: aldosteronoma resolution score (ARS) and primary aldosteronism surgical outcome (PASO) score. Results Ninety-seven of 150 (64.7%) patients achieved complete clinical success after unilateral adrenalectomy in the training cohort and 57 out of 165 (34.5%) in the validation cohort. A nomogram was established incorporating sex, duration of hypertension, aldosterone to renin ratio and target organ damage. The nomogram showed good concordance indices and calibration curves in both Asian and Caucasian cohorts. The area under the receiver operating characteristic curve (AUC) of NBPS for predicting hypertension remission in the training cohort was 0.853 (0.786-0.905), which was superior to ARS [0.745(0.667-0.812), p=0.019] and PASO score [0.747(0.670-0.815), p=0.012]. The AUC of NBPS in the validation cohort was 0.830 (0.764-0.884), which was higher than ARS [0.745 (95% CI 0.672-0.810), p=0.045], but not significantly different from PASO score [0.825 (95% CI 0.758-0.880), p=0.911]. Conclusion The NBPS is useful in predicting clinical outcome for UPA patients, especially in the Asian population.

The prevalence of hyperuricemia has increased rapidly over the past decades. Bisphenol A (BPA) is an environmental endocrine disruptor. We investigated the effects of BPA on uric acid metabolism and its potential mechanisms. Experiments were performed in different animal models, cell cultures, and humans. In 3 different animal models, BPA exposure increased serum and hepatic uric acid with enhanced activity of xanthine oxidase (XO) in liver, whereas the excretion of uric acid was unchanged. Both in vivo and in vitro, BPA-induced uric acid production was decreased after treatment with allopurinol, which is a XO inhibitor. XO led to the accumulation of uric acid after xanthine was added, with the enzyme-catalyzed reaction, which was enhanced by BPA. Altered secondary structures of XO were found by circular dichroism analysis in the conditions of different BPA concentrations. Molecular docking portrayed Asp360 and Lys422 of XO to be the preferred binding sites for BPA. Mutation of both sites significantly blocked the effect of BPA on XO activity. In humans, patients with hyperuricemia exhibited higher levels of serum BPA than subjects without hyperuricemia. These findings demonstrate BPA promotes hyperuricemia by increasing hepatic uric acid synthesis via the activation of XO, probably through direct binding.-Ma, L., Hu, J., Li, J., Yang, Y., Zhang, L., Zou, L., Gao, R., Peng, C., Wang, Y., Luo, T., Xiang, X., Qing, H., Xiao, X., Wu, C., Wang, Z., He, J. C., Li, Q., Yang, S. Bisphenol A promotes hyperuricemia via activating xanthine oxidase.

Context The Endocrine Society Guidelines for the diagnosis of primary aldosteronism (PA) suggest that confirmatory tests (CFT) are not required when the following criteria are met: plasma aldosterone concentration (PAC) is >20 ng/dL, plasma renin is below detection levels, and hypokalemia is present. The evidence for the applicability of the guideline criteria is limited. Objective To develop and validate optimized criteria for sparing CFT in the diagnosis of PA. Design and Setting The optimized criteria were developed in a Chinese cohort using the captopril challenge test, verified by saline infusion test (SIT) and fludrocortisone suppression test (FST), and validated in an Australian cohort. Participants Hypertensive patients who completed PA screening and CFT. Main Outcome Measure Diagnostic value of the optimized criteria. Results In the development cohort (518 PA and 266 non-PA), hypokalemia, PAC, and plasma renin concentration (PRC) were selected as diagnostic indicators by multivariate logistic analyses. The combination of PAC >20 ng/dL plus PRC <2.5 μIU/mL plus hypokalemia had much higher sensitivity than the guideline criteria (0.36 vs 0.11). The optimized criteria remained superior when the SIT or FST were used as CFT. Non-PA patients were not misdiagnosed by either criteria, but the percentage of patients in whom CFT could be spared was higher with the optimized criteria. In the validation cohort (125 PA and 81 non-PA), the sensitivity of the optimized criteria was also significantly higher (0.12 vs 0.02). Conclusions Hypertensive patients with PAC >20 ng/dL, PRC <2.5 μIU/mL, plus hypokalemia can be confidently diagnosed with PA without confirmatory tests.