Nonalcoholic steatohepatitis (NASH) is a major health problem since it often leads to hepatocellular carcinoma. However, the underlying mechanisms of NASH development and subsequent fibrosis have yet to be clarified. We compared comprehensive lipidomic profiles between mice with high fat diet (HFD)-induced steatosis and STAM mice with NASH and subsequent fibrosis. The STAM mouse is a model that demonstrates NASH progression resembling the disease in humans: STAM mice manifest NASH at 8 weeks, which progresses to fibrosis at 12 weeks and finally develop hepatocellular carcinoma. Overall, 250 lipid molecules were detected in the liver using liquid chromatography-mass spectrometry. We found that STAM mice with NASH presented a significantly higher abundance of sphingolipids and lower levels of triacylglycerols than the HFD-fed control mice. The abundance of certain fatty acids in phospholipid side chains was also significantly different between STAM and control mice, although global levels of phosphatidylcholines and phosphatidylethanolamines were comparable. Finally, increase in levels of acylcarnitines and some diacylglycerols was observed in STAM mice toward the fibrosis stage, but not in age-matched control mice. Our study provides insights into the lipid status of the steatotic, NASH and fibrotic liver that would help elucidate the molecular pathophysiology of NASH progression.

The postnatal proliferation and maturation of insulin-secreting pancreatic β-cells are critical for glucose metabolism and disease development in adults. Elucidation of the molecular mechanisms underlying these events will be beneficial to direct the differentiation of stem cells into functional β-cells. Maturation of β-cells is accompanied by increased expression of MafA, an insulin gene transcription factor. Transcriptome analysis of MafA knockout islets revealed MafA is required for the expression of several molecules critical for β-cell function, including Glut2, ZnT8, Granuphilin, Vdr, Pcsk1 and Urocortin 3, as well as Prolactin receptor (Prlr) and its downstream target Cyclin D2 (Ccnd2). Inhibition of MafA expression in mouse islets or β-cell lines resulted in reduced expression of Prlr and Ccnd2, and MafA transactivated the Prlr promoter. Stimulation of β-cells by prolactin resulted in the phosphorylation and translocation of Stat5B and an increased nuclear pool of Ccnd2 via Prlr and Jak2. Consistent with these results, the loss of MafA resulted in impaired proliferation of β-cells at 4 weeks of age. These results suggest that MafA regulates the postnatal proliferation of β-cells via prolactin signaling.

Leptin and ghrelin have been implicated in the pathogenesis of major depression. However, evidence is lacking among apparently healthy people. This study examined the relationship of these appetite hormones to depressive symptoms in a Japanese working population. A cross-sectional study was conducted in 2009 among 497 Japanese employees (287 men and 210 women) aged 20–68 years. Fasting serum leptin and ghrelin levels were measured using a Luminex suspension bead-based multiplexed array. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale. Logistic regression analysis was performed to estimate odds ratio (OR) and 95% confidence interval (CI) for depressive symptoms with adjustment for potential confounders. The prevalence of depressive symptoms (CES-D ≥16) was 26.5% and 33.3% among men and women, respectively. Women in the middle and highest tertiles of leptin levels showed lower odds for depressive symptoms compared with those in the lowest level, although the trend association was not statistically significant (P trend = 0.14). Higher ghrelin levels were associated with increased odds for depressive symptoms in women (P trend = 0.02). The multivariable adjusted OR (95% CI) of having depressive symptoms for the lowest through highest tertiles of ghrelin levels were 1.00 (reference), 1.71 (0.76 - 3.86), and 2.69 (1.16 - 6.28), respectively. Neither leptin nor ghrelin was associated with depressive symptoms in men. Results suggest that lower leptin and higher ghrelin levels may be related to higher prevalence of depressive status among Japanese women.

Purpose: Hyperglycaemia has been identified as major risk factor for diabetic retinopathy (DR). It is widely accepted that the progression of DR is mainly due to a local imbalance of pro‐ versus anti‐angiogenic factors in the retina. In this study, we investigated whether retinal pigment epithelial (RPE) cells produced pro‐angiogenic factors under high glucose (HG) conditions in vitro. Methods: Cultured human retinal endothelial (RE) cells were exposed to conditioned medium from retinal pigment epithelium cells (ARPE‐19) grown in HG medium and assessed for tube formation. Based on the expression profiles of ARPE‐19, we investigated whether ANGPTL4 was a major angiogenic factor released from ARPE‐19 under HG conditions using cultured human RE cells as the test system for experiments with recombinant protein, conditioned medium from ARPE‐19 and RNA interference (RNAi). Results: The conditioned medium from ARPE‐19 cultured under HG conditions promoted tube formation of cultured human RE cells. GeneChip analysis showed that ANGPTL4 was one of the highest upregulated genes under HG conditions. In addition, recombinant ANGPTL4 promoted all of the elements of angiogenesis in human RE cells in vitro. The results of experiments using conditioned medium from ARPE‐19 combined with RNAi demonstrated that ANGPTL4 was a major angiogenic factor released from ARPE‐19 under HG conditions. Conclusions: ANGPTL4 was induced by high glucose in RPE cells and exhibited potent angiogenic activity on RE cells. Our results are unique and may potentially add a new candidate to the long list of molecules involved in diabetic retinopathy.