Dan Ye

TCF7L2 involvement in estradiol- and progesterone-modulated islet and hepatic glucose homeostasis

To evaluate the role of TCF7L2, a key regulator of glucose homeostasis, in estradiol (E2) and progesterone (P4)-modulated glucose metabolism, mouse insulinoma cells (MIN6) and human liver cancer cells (hepG2 and HUH7) were treated with physiological concentrations of E2 or P4 in the up- and down-regulation of TCF7L2. Insulin/proinsulin secretion was measured in MIN6 cells, while glucose uptake and production were evaluated in liver cancer cells. E2 increased insulin/proinsulin secretion under both basal and stimulated conditions, whereas P4 increased insulin/proinsulin secretion only under glucose-stimulated conditions. An antagonistic effect, possibly concentration-dependent, of E2 and P4 on the regulation of islet glucose metabolism was observed. After E2 or P4 treatment, secretion of insulin/proinsulin was positively correlated with TCF7L2 protein expression. When TCF7L2 was silenced, E2- or P4-promoted insulin/proinsulin secretion was significantly weakened. Under glucotoxicity conditions, overexpression of TCF7L2 increased insulin secretion and processing. In liver cancer cells, E2 or P4 exposure elevated TCF7L2 expression, enhanced the activity of insulin signaling (pAKT/pGSK), reduced PEPCK expression, subsequently increased insulin-stimulated glucose uptake, and decreased glucose production. Silencing TCF7L2 eliminated effects of E2 or P4. In conclusion, TCF7L2 regulates E2- or P4-modulated islet and hepatic glucose metabolism. The results have implications for glucose homeostasis in pregnancy.

Polymorphisms in TCF7L2 gene are associated with gestational diabetes mellitus in Chinese Han population.

This study aimed to investigate the possible association between diabetes susceptibility gene transcription factor 7-like 2 (TCF7L2) and gestational diabetes mellitus (GDM) in a Chinese Han population. A total of 556 GDM patients and 500 Non-GDM were included. Eighteen single nucleotide polymorphisms (SNPs) were evaluated. Fifteen tag SNPs were selected from HapMap CHB database with a minor allele frequency of >0.2 and r2 of >0.8. Three additional SNPs were also chosen because these SNPs are associated with type 2 diabetes in East Asians. TCF7L2 rs290487, rs6585194, and rs7094463 polymorphisms were found to be significantly associated with GDM. In multivariate analysis, rs290487 genetic variation (OR = 2.686 per each C allele, P = 0.002), pre-BMI > 24 kg/m2 (OR = 1.592, P = 0.018), age > 25 years (OR = 1.780, P = 0.012) and LDL-C > 3.6 mmol/L (OR = 2.034, P = 0.009) were identified as independent risk factors of GDM, rs7094463 genetic variation (OR = 0.429 per each G allele, P = 0.005) was identified as independent protect factor of GDM. This finding suggests that TCF7L2 rs290487, and rs7094463 were a potential clinical value for the prediction of GDM.

A missense mutation in the arginine‐vasopressin neurophysin‐II gene causes autosomal dominant neurohypophyseal diabetes insipidus in a Chinese family

Familial neurohypophyseal diabetes insipidus, an autosomal dominant disorder, is mostly caused by mutations in the genes that encode AVP or its intracellular binding protein, neurophysin‐II. The mutations lead to aberrant preprohormone processing and progressive destruction of AVP‐secreting cells, which gradually manifests a progressive polyuria and polydipsia during early childhood, and a disorder of water homeostasis.

Plasma miR-17, miR-20a, miR-20b and miR-122 as potential biomarkers for diagnosis of NAFLD in type 2 diabetes mellitus patients

Aims: Type 2 diabetes mellitus (T2DM), with non‐alcoholic fatty liver disease (NAFLD) complication, may aggravate the disturbance of metabolism, increase the risk of non‐alcoholic steatohepatitis, and promote the progress of liver fibrosis. Therefore, early detection of NAFLD in T2DM patients is critical in avoiding the adverse effects of the complication. This study aimed to identify circulating miRNAs for early diagnosis of the complication. Materials and methods: Plasma miRNA expression profiles of T2DM patients complicated with or without NAFLD were examined by miRNA array analysis and then were validated by qRT‐PCR. A new index for prediction the presence of NAFLD was developed based on the result of multivariate logistic regression analysis. STZ and high fat diet were used for construction a rat model of T2DM complicated with NAFLD. Key findings: Plasma miR‐17, miR‐20a, miR‐20b, and miR‐122 were up‐regulated in T2DM patients with NAFLD complicated compared in those without NAFLD (P < 0.05). Moreover, the data from the rat model further showed that the above miRNAs were more sensitive than traditional serological markers for predicting the complication. Meanwhile, in order to improve the diagnostic accuracy, we try to construct an AUC by using the new index, 24.852 × WHR‐1.121 × miR122 + 1.988 × LDL‐21.838, which was significantly higher than a chance assignment (asymptotic significance P < 0.001) for predicting the presence of NAFLD. Significance: Plasma miRNAs and the new index involving WHR, LDL, and miR‐122 are potential novel tools for the early diagnosis and risk estimation of NAFLD in T2DM patients.

MiR-17 family-mediated regulation of Pknox1 influences hepatic steatosis and insulin signaling

The aberrant expression of Pknox1 is associated with hepatic glucose and lipid dysmetabolism status of type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanism causing Pknox1 overexpression in this pathological status remains unclear. By using miRNA target prediction programs, we found that the 3′‐UTR of the Pknox1 mRNA sequence contains highly conserved target sites of miR‐17 family. In a rat model of streptozotocin and high‐fat diet‐induced T2DM and NAFLD complication, the increased hepatic expression of Pknox1 was consistent with decreased expressions of miR‐17 family, especially miR‐17 and miR‐20a. Furthermore, an inverse correlation was observed between Pknox1 and miR‐17 and miR‐20a in free fatty acids‐induced hepatocyte steatosis. Dual‐luciferase reporter assay further showed that Pknox1 was a valid target gene of miR‐17 family. The ectopic expression of miR‐17 or miR‐20a could markedly suppress Pknox1 expression in hepatocytes. MiR‐17 or miR‐20a overexpression also resulted in significantly enhanced insulin sensitivity and reduced hepatocyte steatosis in HepG2 and L02 cells, which were determined by altered phosphorylation on insulin receptor signaling pathway proteins and decreased intracellular triglyceride and lipid accumulation, respectively. These data implicate the upregulated hepatic expression of Pknox1 in T2DM complicated with NAFLD may be caused by the reduced expression of miR‐17 family, indicating that developing miRNA‐mediated regulation strategies on Pknox1 may provide new therapeutic options for metabolic disease.

Role of miR-223 in the pathophysiology of liver diseases

MiRNAs are small, noncoding RNAs, which can regulate gene expression posttranscriptionally, and they have emerged as key factors in disease biology by aiding in disease development and progression. MiR-223 is highly conserved during evolution and it was first described as a modulator of hematopoietic lineage differentiation. MiR-223 has an essential part in inflammation by targeting the nuclear factor-κB pathway and the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome. Recent studies have shown that miR-223 expression is deregulated in various types of liver diseases, including hepatitis virus infections, alcohol-induced liver injury, drug-induced liver injury, non-alcoholic fatty liver disease, cirrhosis, and hepatocellular carcinoma. As inflammatory and immune factors are involved in the occurrence and progress of liver diseases, deregulated miR-223 may participate in the pathogenesis of these conditions by influencing neutrophil infiltration, macrophage polarization, and inflammasome activation. This review first summarizes the present understanding of the biological functions of miR-223, including its gene location and transcription regulation, as well as its physiological role in hematopoietic differentiation. This review then focuses on the role of miR-223 in liver pathophysiology and its potential applications as a diagnostic biomarker and therapeutic target in liver diseases.Liver disease: a tiny trigger for liver damageA tiny RNA molecule involved with gene regulation may offer an appealing target for diagnosing and treating various liver diseases. MicroRNA-223 (miR-223) was first identified as controlling gene activity in a wide variety of immune cells. A review from researchers led by Yanning Liu at China’s Zhejiang University in Hangzhou details how abnormal miR-223 also contributes to liver damage in a variety of conditions, although questions still remain about how it functions in different liver disorders. The authors highlight studies linking miR-223 with the development of fibrosis and cirrhosis, and with the inflammatory response to injury from drugs, alcohol, or infection. This could make this microRNA a useful diagnostic biomarker. The authors also identify therapeutic opportunities to modulate this molecule, referring to several studies on the manipulation of miR-223 to treat hepatitis.

AMSC-derived exosomes alleviate lipopolysaccharide/d-galactosamine-induced acute liver failure by miR-17-mediated reduction of TXNIP/NLRP3 inflammasome activation in macrophages

Background Mesenchymal stem cell (MSC)-derived exosome administration has been considered as a novel cell-free therapy for liver diseases through cell-cell communication. This study was aimed to determine the effects and mechanisms of AMSC-derived exosomes (AMSC-Exo) for acute liver failure (ALF) treatment. Methods AMSC-Exo were intravenously administrated into the mice immediately after lipopolysaccharide and D-galactosamine (LPS/GalN)-exposure and their effects were evaluated by liver histological and serum biochemical analysis. To elucidate its mechanisms in ALF therapy, the expression levels of miRNAs and inflammasome-related genes in macrophages were evaluated by qPCR and Western blot analysis, respectively. The exosomes from miR-17-knockdowned AMSCs (AMSC-ExomiR-17-KD) were used for further determine the role of miR-17 in AMSC-Exo-based therapy. Findings AMSC-Exo administration significantly ameliorated ALF as determined by reduced serum alanine aminotransferase and aspartate aminotransferase levels and hepatic inflammasome activation. Further experiments revealed that AMSC-Exo were colocalized with hepatic macrophages and could reduce inflammatory factor secretion by suppressing inflammasome activation in macrophages. Moreover, miR-17, which can suppress NLRP3 inflammasome activation by targeting TXNIP, was abundant in AMSC-Exo cargo. While, the therapeutic effects of AMSC-ExomiR-17-KD on ALF were significantly abolished as they could not effectively suppress TXNIP expression and consequent inflammasome activation in vitro and in vivo. Interpretation: Exosome-shuttled miR-17 plays an essential role in AMSC-Exo therapy for ALF by targeting TXNIP and suppressing inflammasome activation in hepatic macrophages. AMSC-Exo-based therapy may present as a promising approach for TXNIP/NLRP3 inflammasome-related inflammatory liver diseases. Fund Key R&D projects of Zhejiang province (2018C03019) and National Natural Science Fund (81470851 and 81500616).

Analysis of a Chinese pedigree with trichorhinophalangeal syndrome derived from a missense mutation in the TRPS1 gene

lizumab. We congratulate them on this very interesting paper, both in the cases and the review, but the report also raised some questions that we would like to address. First, the authors state that to their knowledge, there are only eight published case reports of idiopathic angiooedema treated with omalizumab in the literature to date. However, and obviously because of the delay between the acceptance and the publication of their paper, they did not mention our recent report on another eight patients with isolated angio-oedema refractory to other treatments, for which only omalizumab was successful. Second, we would like to draw attention to the high doses used by Pedraz Mu~ noz et al., as all the patients in our study responded without delay at monthly doses of 300 mg, and maintenance could be carried out at doses as low as 75 mg, with a wide time range, from 3 to 16 weeks. Likewise, in the previously conducted randomized studies on chronic urticaria and angiooedema, monthly doses of 300 mg were sufficient to control angio-oedema (and in some cases superior to placebo or other lower doses). Finally, a major analytical finding by Pedraz Mu~ noz et al. was the level of total IgE, which ranged between 150 and 875 kU/L in their patients. This might suggest an atopic condition and/or a causal allergy, which was not further investigated by the authors. In our opinion, an accurate allergological study could help exclude other underlying conditions, such as allergenic agents (foods, drugs other than angiotensin-converting enzyme inhibitors, latex, Anisakis simplex), or nonallergenic agents (nonsteroidal anti-inflammatory drugs, opioids, infections) able to cause recurrent angio-oedema in our environment. Perhaps the subsequent elimination of avoidable triggers might make unnecessary the continuous (and expensive) use of omalizumab in these patients.