GPR119 activation by DA-1241 alleviates hepatic and systemic inflammation in MASH mice through inhibition of NFκB signaling.

BACKGROUND AND PURPOSE: GPR119 activation has been suggested to improve hyperglycemia, dyslipidemia and hepatic steatosis. But its therapeutic potential for metabolic dysfunction-associated steatohepatitis (MASH) are underexplored. Here, we investigated the effects of DA-1241, a novel GPR119 agonist, on MASH and explored its underlying mechanism of anti-inflammatory effects. EXPERIMENTAL APPROACH: The in vivo anti-MASH effect was assessed by examining the preventive effect in MS-MASH and Ob-MASH mice and the therapeutic effect in MASH with severe hyperglycemia and diet-induced obese (DIO)-MASH mice. Histological and biochemical changes in liver tissue were assessed. Both plasma and hepatic biomarkers related to inflammation and fibrosis were comprehensively analyzed. To understand its mode of action, changes in NFκB signaling were determined in HepG2 and THP-1 cells. KEY RESULTS: DA-1241 attenuated MASH progression and alleviated the MASH phenotypes in MASH mouse models with different etiologies, regardless of glucose-lowering activity. In DIO-MASH mice, DA-1241 significantly reduced biochemical parameters related to steatosis, inflammation and fibrosis in the liver with reduced plasma liver enzymes. When used in combination with a dipeptidyl peptidase 4 (DPP4) inhibitor, DA-1241 further improved the MASH phenotype by increasing endogenous glucagon-like peptide-1 effect. Notably, DA-1241 alone and in combination reduced liver inflammation and restored inflammation-related hepatic gene expression, leading to remission of systemic inflammation as assessed by plasma inflammatory cytokines and chemokines. We demonstrated that DA-1241 reduces macrophage differentiation through downregulation of NFκB signaling by activating GPR119. CONCLUSION: Our data suggest the therapeutic potential of DA-1241, alone and in combination with a DPP4 inhibitor, for MASH.

A novel GPR119 agonist DA-1241 preserves pancreatic function via the suppression of ER stress and increased PDX1 expression.

DA-1241 is a novel small molecule G protein-coupled receptor 119 (GPR119) agonist in early clinical development for type 2 diabetic patients. This study aimed to elucidate the pharmacological characteristics of DA-1241 for its hypoglycemic action. DA-1241 potently and selectively activated GPR119 with enhanced maximum efficacy. DA-1241 increased intracellular cAMP in HIT-T15 insulinoma cells (EC50, 14.7 nM) and increased insulin secretion (EC50, 22.3 nM) in association with enhanced human insulin promoter activity. Accordingly, postprandial plasma insulin levels were increased in mice after single oral administration of DA-1241. Postprandial glucose excursion was significantly reduced by single oral administration of DA-1241 in wild-type mice but not in GPR119 knockout mice. GLP-1 secretion was increased by DA-1241 treatment in mice. Thus, upon combined sitagliptin and DA-1241 treatment in high-fat diet/streptozotocin (HFD/STZ)-induced diabetic mice, plasma active GLP-1 levels were synergistically increased. Accordingly, blood glucose and triglyceride levels were significantly lowered both by DA-1241 and sitagliptin alone and in combination. Immunohistochemical analysis revealed that ß-cell mass with reduced PDX1 levels in the islets from HFD/STZ diabetic mice was significantly preserved by DA-1241, whereas increased glucagon and BiP levels were significantly suppressed. In HIT-T15 insulinoma cells subjected to ER stress, decreased cell viability was significantly rescued by treatment with DA-1241. Additionally, increased apoptosis was largely attenuated by DA-1241 by inhibiting BiP and CHOP expression through suppression of p38 MAPK. In conclusion, these studies provide evidence that DA-1241 can be a promising antidiabetic drug by potentially preserving pancreatic functions through suppressing ER stress and increasing PDX1 expression.

Predictors of adverse outcome in patients with frequent premature ventricular complexes: The ABC-VT risk score.

BACKGROUND: No independently validated score currently exists for risk stratification of patients with frequent premature ventricular complexes (PVCs). OBJECTIVES: The purpose of this study was to develop a risk score to predict adverse events in patients with frequent PVCs. METHODS: We analyzed consecutive patients between 2012 and 2017 undergoing 14-day continuous monitoring with frequent PVCs (>5%) and concurrent echocardiography. We performed binary logistic regression to determine multivariate predictors of adverse left ventricular remodeling (left ventricular ejection fraction [LVEF] <45% or left ventricular end-diastolic volume index >75 mL/m2). A risk score was created using the log(odds ratio (OR)) of these predictors and validated prospectively to determine the risk of future adverse events in those with baseline LVEF >45%. An adverse event was defined as LVEF decline by 10%, heart failure hospitalization, or cardiovascular mortality. Two validation cohorts were used: follow-up from the original derivation cohort (cohort 1) and an independent Korean PVC registry (cohort 2). RESULTS: The derivation cohort comprised 206 patients with a mean PVC burden of 11.6% ± 6.2% and considerable daily fluctuation (minimum burden 7.3% ± 6.2% vs maximum 17.9% ± 8.0%). Independent predictors of adverse remodeling were as follows: superiorly directed PVC axis (OR 2.7; 1 point), PVC burden 10%-20% (OR 3.5; 2 points) and >20% (OR 4.4; 3 points), PVC coupling interval >500 ms (OR 4.7; 4 points), nonsustained ventricular tachycardia (OR 5.3; 4 points), which form the ABC-VT risk score. This score predicted future adverse events in both validation cohorts: cohort 1, hazard ratio 1.43; 95% confidence interval 1.19-1.73; P < .001 and cohort 2, hazard ratio 1.22; 95% confidence interval 1.05-1.42; P = .01. CONCLUSION: The ABC-VT score is a simple tool that predicts adverse left ventricular remodeling and future clinical deterioration in patients with frequent PVCs.

Efficacy of evogliptin and cenicriviroc against nonalcoholic steatohepatitis in mice: a comparative study.

Dipeptidyl peptidase (DPP)-4 inhibitors, or gliptins, are a class of oral hypoglycemic drugs that have been widely used as a second-line treatment for type 2 diabetes. Gliptins, which were introduced for clinical use a decade ago, have been shown to be beneficial against nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH) in animals and humans. Cenicriviroc (CVC), a dual antagonist of C-C chemokine receptor type 2 and 5, is currently under investigation against NASH and fibrosis. It was previously discovered that evogliptin (EVO) reduces hepatic steatosis in diet-induced obese animals but the effectiveness of EVO on NASH remains unexplored. Here, we compared the effectiveness of EVO and CVC against NASH and fibrosis in mice fed a high-fat and high-fructose diet (HFHF). Biochemical and histological analyses showed that mice fed a HFHF for 20 weeks developed severe hepatic steatosis and inflammation with mild fibrosis. Administration of EVO (0.2% wt/wt) for the last 8 weeks of HFHF feeding significantly reduced hepatic triglyceride accumulation, inflammation, and fibrosis as well as restored insulin sensitivity, as evidenced by lowered plasma insulin levels and the improvement in insulin tolerance test curves. Treatment of mice with CVC (0.1% wt/wt) inhibited hepatic inflammation and fibrogenesis with similar efficacy to that of EVO, without affecting hepatic steatosis. CVC treatment also reduced plasma insulin concentrations, despite no improvement in insulin tolerance. In conclusion, EVO administration efficiently ameliorated the development of NASH and fibrosis in HFHF-fed mice, corroborating its therapeutic potential.

NR1D1 Recruitment to Sites of DNA Damage Inhibits Repair and Is Associated with Chemosensitivity of Breast Cancer.

DNA repair capacity is critical for survival of cancer cells upon therapeutic DNA damage and thus is an important determinant of susceptibility to chemotherapy in cancer patients. In this study, we identified a novel function of nuclear receptor NR1D1 in DNA repair, which enhanced chemosensitivity in breast cancer cells. NR1D1 inhibited both nonhomologous end joining and homologous recombination double-strand breaks repair, and delayed the clearance of γH2AX DNA repair foci that formed after treatment of doxorubicin. PARylation of NR1D1 by PARP1 drove its recruitment to damaged DNA lesions. Deletion of the ligand binding domain of NR1D1 that interacted with PARP1, or treatment of 6-(5H)-phenanthridinone, an inhibitor of PARP1, suppressed the recruitment of NR1D1 to DNA damaged sites, indicating PARylation as a critical step for the NR1D1 recruitment. NR1D1 inhibited recruitment of the components of DNA damage response complex such as SIRT6, pNBS1, and BRCA1 to DNA lesions. Downregulation of NR1D1 in MCF7 cells resulted in resistance to doxorubicin, both in vitro and in vivo Analysis of four public patient data sets indicated that NR1D1 expression correlates positively with clinical outcome in breast cancer patients who received chemotherapy. Our findings suggest that NR1D1 and its ligands provide therapeutic options that could enhance the outcomes of chemotherapy in breast cancer patients. Cancer Res; 77(9); 2453-63. ©2017 AACR.

22-S-Hydroxycholesterol protects against ethanol-induced liver injury by blocking the auto/paracrine activation of MCP-1 mediated by LXRα.

Chronic ethanol consumption causes hepatic steatosis and inflammation, which are associated with liver hypoxia. Monocyte chemoattractant protein-1 (MCP-1) is a hypoxia response factor that determines recruitment and activation of monocytes to the site of tissue injury. The level of MCP-1 is elevated in the serum and liver of patients with alcoholic liver disease (ALD); however, the molecular details regarding the regulation of MCP-1 expression are not yet understood completely. Here, we show the role of liver X receptor α (LXRα) in the regulation of MCP-1 expression during the development of ethanol-induced fatty liver injury, using an antagonist, 22-S-hydroxycholesterol (22-S-HC). First, administration of 22-S-HC attenuated the signs of liver injury with decreased levels of MCP-1 and its receptor CCR2 in ethanol-fed mice. Second, hypoxic conditions or treatment with the LXRα agonist GW3965 significantly induced the expression of MCP-1, which was completely blocked by treatment with 22-S-HC or infection by shLXRα lentivirus in the primary hepatocytes. Third, over-expression of LXRα or GW3965 treatment increased MCP-1 promoter activity by increasing the binding of hypoxia-inducible factor-1α to the hypoxia response elements, together with LXRα. Finally, treatment with recombinant MCP-1 increased the level of expression of LXRα and LXRα-dependent lipid droplet accumulation in both hepatocytes and Kupffer cells. These data show that LXRα and its ligand-induced up-regulation of MCP-1 and MCP-1-induced LXRα-dependent lipogenesis play a key role in the autocrine and paracrine activation of MCP-1 in the pathogenesis of alcoholic fatty liver disease, and that this activation may provide a promising new target for ALD therapy.