Wentworth Mohamad (sparkshape1)

BACKGROUND & AIMS RNA G-quadruplexes (RG4s) appear to be important in post-transcriptional gene regulation, but their pathophysiological functions remain unknown. MicroRNA-26a (miR-26a) is emerging as a therapeutic target for various human diseases, however the mechanisms underlying endogenous miR-26a regulation are poorly understood. Here we report a role of RG4 in miR-26a expression and function in vitro and in vivo. METHODS Putative RG4s within liver-enriched miRNAs were predicted by bioinformatical analysis, and the presence of RG4 structure in miR-26a-1 precursor (pre-miR-26a-1) was further analyzed by biophysical and biochemical methods. RG4 stabilizers, pre-miR-26a-1 overexpression plasmids, and luciferase reporter assay were used to assess the effect of RG4 on pre-miR-26a-1 maturation. Both miR-26a knockin and knockout mouse models were employed to investigate the influence of this RG4 on miR-26a expression and function. Moreover, the interaction between RG4 in pre-miR-26a-1 and DEAH-box helicase 36 (DHX36) was determined by biophysical and molecular methods. Finally, the miR-26a processing and DHX36 expression were quantified in the livers from genetic and diet-induced obese mouse models. RESULTS We identify a guanine-rich sequence in pre-miR-26a-1 that can fold into RG4 structure. This RG4 impairs pre-miR-26a-1 maturation, resulting in a decrease in miR-26a expression and subsequently an increase in miR-26a cognate targets. In line with known miR-26a function, this RG4 can regulate hepatic insulin sensitivity and lipid metabolism in vitro and in vivo. Furthermore, we reveal that DHX36 can bind and unwind this RG4 structure, thereby enhancing miR-26a maturation. Intriguingly, there is a concordant decrease of miR-26a maturation and DHX36 expression in obese mouse livers. CONCLUSIONS Our findings define a dynamic DHX36/RG4/miR-26a regulatory axis during obesity, highlighting an important role of RG4 in physiology and pathology. BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC. METHODS AESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) ≥2×ULN and total bilirubin less then 2.5×ULN. Patients were randomized 111 to receive placebo, OCA 1.5-3 mg, or OCA 5-10 mg once daily for a 24-week double-blind phase followed by a 2-year, long-term safety extension (LTSE). Primary endpoints were change in ALP from baseline to week 24, and safety. RESULTS The intent-to-treat population comprised 76 patients randomized to placebo (n=25), OCA 1.5-3 mg (n=25), and OCA 5-10 mg (n=26). At week 24, serum ALP was significantly reduced with OCA 5-10 mg vs. placebo least-square (LS) mean difference = ‒83.4 (standard error [SE]=40.3) U/L, 95% CI -164.28, -2.57; p=0.043. Serum ALP was not significantly reduced with OCA 1.5-3 mg vs. placebo at week 24 (LS mean [SE] difference = -78.29 [41.81] U/L, 95% CI -162.08, 5.50; p=0.067). Total bilirubin remained comparable to baseline in all groups. The most common treatment-emergent adverse event was dose-related pruritus (placebo, 46%; OCA 1.5-3 mg, 60%; OCA 5-10 mg, 67%). Reductions in ALP were maintained during the LTSE, and no new safety signals emerged. CONCLUSIONS Treatment with OCA 5-10 mg reduced serum ALP in patients with PSC. Mild to moderate dose-related pruritus was the most common adverse event. V.BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D) and obesity are epidemiologically correlated with each other but the causal inter-relationships among them remains incompletely understood. We aim to explore the causal relationships among the