METTL3 inhibits hepatic insulin sensitivity via N6-methyladenosine modification of Fasn mRNA and promoting fatty acid metabolism.

Type 2 diabetes (T2D) is characterized by lack of insulin, insulin resistance and high blood sugar. However, the underlying mechanisms of insulin resistance during T2D development remains unclear. As the most common mRNAs modification, N6-Methyladenosine (m6A) is involved in many of pathological processes in aging disease. However, it remains unclear whether m6A is involved in T2D development and what is the regulatory mechanism. This study is aimed to illustrate the roles of m6A and its methyltransferase METTL3 in the regulation of blood glucose homeostasis and insulin sensitivity. The results showed that m6A methylated RNA level and its N6-methyladenosine methylase METTL3 were consistently up-regulated in the liver tissues from patients with T2D. Moreover, both m6A methylated RNA and METTL3 levels showed positive correlation with HOMA-IR and negative correlation with HOMA-ß. The m6A methylated RNA and METTL3 levels were also up-regulated in mouse with 16 weeks high-fat diet (HFD), compared with mice fed a standard chow diet (CD). Hepatocyte-specific knockout of METTL3 in mice fed a HFD improved insulin sensitivity and decreased fatty acid synthesis. Furthermore, mechanism analysis demonstrates that METTL3 silence decreased the m6A methylated and total mRNA level of Fatty acid synthase (Fasn), subsequently inhibited fatty acid metabolism. Adeno-associated virus mediated Fasn overexpression in METTL3 knockout mice abrogates the improved insulin sensitivity and decreased fatty acid synthesis. Collectively, these results reveal that RNA N6-methyladenosine methylase METTL3 inhibits hepatic insulin sensitivity via N6-methylation of Fasn mRNA and promoting fatty acid metabolism.

[Changes of intercellular adhesion molecule-1 and E-selectin levels in plasma of uremic patients treated with maintaining hemodialysis].

AIM: To detect the levels of ICAM-1 and E-selectin in plasmas from uremic patients treated by means of maintaining hemodialysis (MHD) and explore the pathological mechanism of atherosclerosis in MHD patients. METHODS: The levels of ICAM-1 and E-selectin in plasmas from the 105 MHD patients and 25 healthy persons (control group) were detected by dual antibody sandwich ELISA. The cervical atherosclerosis of the patients was examined by type B ultrasonography. Simultaneously, the blood pressures of the patients and control group were taken and recorded, as well as the biochemical criterions in their blood were detected. RESULTS: (1) The plasma levels of ICAM-1 and E-selectin in MHD patients were significantly higher than those in the control group, respectively (P < 0.01), and in MHD group the above indexes in patients with cervical atherosclerosis were significantly higher than those without cervical atherosclerosis (P < 0.01,P < 0.05). (2) In MHD group, the plasma ICAM-1 level was positively correlated with E-selectin and triglycerides (TG) levels(r = 0.62 and 0.60, respectively), and with the diastolic pressure(r = 0.41,P < 0.05). CONCLUSION: The impairment of vascular endothelial function was obvious in uremic patients with MHD. The changes of ICAM-1 and E-selectin could be accepted as biochemical criterions of vascular endothelial injury. The two adhesion molecules have close relationship with atherosclerosis in MHD patients.

[The effect of continuous high-volume hemofiltration therapy on TNF-alpha of pancreatitis patients complicated with acute renal function failure].

AIM: To explore the role of continuous high-volume renal replacement therapy(HV-CRRT) in serum TNF-alpha removal. METHODS: 13 panceatitis patients complicated with acute renal failure were treated by continuous venovenous hemofiltration (CVVH), and they were divided into two groups according to the substitution rate during CVVH. The substitution rate of group I (8 cases) was 2 L/h, the that of group II(5 cases) was 4 L/h. 1ml blood samples were taken from the post-filter at 0,1,2,3,6 and 24 h after CRRT, respectively. The TNF-alpha level produced from endotoxin-induced periphral blood mononuclear cells (PBMCs) was detected by ELISA. Ultrafiltrate samples were co-incubated with donor's whole blood containing ET so as to detect suppression activity of ultrafiltrate. RESULTS: Production of TNF-alpha by ET-induced PBMCs was significantly suppressed in group I and II. During CVVH treatment, suppressed ET-induced TNF-alpha production increased variously in the first 3 h, and then decreased gradually. In contrast, the increased levels of ET-induced TNF-alpha production in group II were higher than that in group I, and maintained a higher level until 24 h after CVVH therapy. The ultrafiltrate from group I had no suppressing activity, but the ultrafiltrate from group II suppressed ET-induced TNF-alpha production, the suppression rate was (15+/-6)%. CONCLUSION: HV-CRRT is more effective than standard CRRT in removal of inflammatory mediators. The mediators are removed mainly by filter membrane adsorption, and maybe partly by convection. Therefore, HV-CRRT with large-pore filter membranes is an effective way in removal of inflammatory mediators.

[The significance of fluorescent patterns of antineutrophil cytoplasmic antibodies (ANCA) in renal diseases].

AIM: To further explore significance of fluorescent patterns of antineutrophil cytoplasmic antibodies in renal diseases. METHODS: ANCA fluorescent patterns and its target antigens in sera of 251 patients with renal diseases were detected by indirect immunofluorescence (IIF) and ELISA. RESULTS: The positive percentage of ANCA is 20.3% (51/251), in which 3.98%(10/251) is cANCA, 11.95% (30/251) pANCA and 4.38%(11/251) aANCA. CONCLUSION: The simultaneous screening for ANCA and its target antigens by IIF and ELISA can increase the positive percentage of ANCA in renal diseases. This novel screening strategy is able to distinguish atypical ANCA(aANCA) from pANCA with ANA and therefore useful for differential diagnosis between vasculitis and autoimmune diseases.