Gestational bisphenol A exposure induces fatty liver development in male offspring mice through the inhibition of HNF1b and upregulation of PPARγ.

Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) associated with non-alcoholic fatty liver disease (NAFLD). The effects of gestational BPA exposure on hepatic lipid accumulation in offspring are not fully understood. Here, we investigate the sex-dependent effects of gestational BPA exposure on hepatic lipid and glucose metabolism in the offspring of mice to reveal the mechanisms underlying gestational BPA exposure-associated NAFLD. Pregnant mice were administered gavage with or without 1 µg kg-1 day-1 BPA at embryonic day 7.5 (E7.5)-E16.5. Hepatic glucose and lipid metabolism were evaluated in these models. Both male and female offspring mice exhibited hepatic fatty liver after BPA treatment. Lipid accumulation and dysfunction of glucose metabolism were observed in male offspring. We revealed abnormal expression of lipid regulators in the liver and that inhibition of peroxisome proliferator-activated receptor γ (PPARγ) repressed hepatic lipid accumulation induced by gestational BPA exposure. We also found a sex-dependent decrease of hepatocyte nuclear factor 1b (HNF1b) expression in male offspring. The transcriptional repression of PPARγ by HNF1b was confirmed in L02 cells. Downregulation of HNF1b, upregulation of PPARγ, and subsequent upregulation of hepatic lipid accumulation were essential for NAFLD development in male offspring gestationally exposed to BPA as well as BPA-exposed adult male mice. Dysregulation of the HNF1b/PPARγ pathway may be involved in gestational BPA exposure-induced NAFLD in male offspring. These data provide new insights into the mechanism of gestational BPA exposure-associated sex-dependent glucose and lipid metabolic dysfunction. Graphical abstract Schematic of the mechanism of gestational BPA exposure-induced glucose and lipid metabolic dysfunction.

Oleanolic acid attenuates PCBs-induced adiposity and insulin resistance via HNF1b-mediated regulation of redox and PPARγ signaling.

Polychlorinated biphenyls (PCBs) exposure is closely associated with obesity and diabetes. However, the mechanism of PCBs-induced adiposity and insulin resistance is not clear and the intervention is limited. We have found that oleanolic acid (OA) is a natural triterpenoid, possessing antioxidant and anti-diabetic activity, and hepatocyte nuclear factor 1b (HNF1b) is an important regulator of glucose and lipid metabolism. The present study aimed to investigate the effect of OA on Aroclor 1254-induced adiposity and insulin resistance and explore the possible involvement of HNF1b. We showed that OA significantly attenuated Aroclor 1254-induced insulin resistance and abnormal changes of glucose and lipid parameters. OA inhibited the increase of adipose weight and adipocyte size in Aroclor 1254-treated mice and repressed adipocyte differentiation in vitro. In addition, OA markedly inhibited Aroclor 1254-induced increase of ROS, oxidant products, NOX4 expression, decrease of SOD1, SOD2, GCLC, GCLM and Gpx1 expression, and increase of PPARγ signaling. Aroclor 1254 resulted in a decrease of HNF1b expression in adipose of mice and adipocytes, which was inhibited by OA. Upregulation of HNF1b blocked Aroclor 1254-induced oxidative stress, adipocyte differentiation and insulin resistance. Downregulation of HNF1b inhibited OA-induced protective effects against Aroclor 1254-associated oxidative stress, adipocyte differentiation and insulin resistance. The antioxidant Vitamin C reduced Aroclor 1254-induced ROS generation in vitro, but had no significant effect on HNF1b expression, oxidative stress and metabolic dysfunction in vivo. OA could inhibit PCBs mixture-induced oxidative injury and glucose/lipid metabolic dysfunction via HNF1b-mediated regulation of redox homeostasis. Our data suggest that HNF1b is a new on/off switch of redox homeostasis and OA-stimulated HNF1b-endogenous antioxidant activity is a potential option for the intervention of PCBs exposure-related adiposity and insulin resistance.

Hordenine protects against hyperglycemia-associated renal complications in streptozotocin-induced diabetic mice.

The worldwide prevalence of diabetes and associated metabolic diseases has dramatically increased. Pharmacological treatment of diabetes is still limited. Hordenine (HOR), a phenethylamine alkaloid, is a natural constituent in many plants. The present study was designed to explore the possible anti-diabetic effect of HOR in streptozotocin (STZ)-induced diabetic mice. Combined treatment of HOR and insulin significantly reduced fasting and postprandial blood glucose level in diabetic mice. HOR and insulin did not show evident protective effect against structural and functional injuries of pancreas. Renal histological and functional injuries were significantly improved by HOR or insulin treatment. Moreover, combined treatment of HOR and insulin resulted in a more significant amelioration of renal histological and functional injuries in diabetic mice. HOR induced a decrease of renal IL-1α/ß and IL-6 expression, and a reduction of Col1α1 and MMP9 expression and PAS-stained mesangial expansion in glomeruli of diabetic mice. In diabetic mice, HOR significantly decreased Nrf2 expression and increased hnRNPF and hnRNPK expression in kidney. Moreover, HOR showed a synergistic effect with insulin on the expression of these regulators. Renal ROS level and TBARS content in diabetic mice were decreased by HOR. The reduction of renal expression of antioxidant enzymes in diabetic mice was inhibited by HOR and insulin. Furthermore, HOR and insulin function synergistically to play an antioxidant role against oxidative injury in diabetic nephropathy. In conclusion, to the best of our knowledge, we, for the first time, found the anti-diabetic, anti-inflammatory, and anti-fibrotic role of HOR in combination with insulin. HOR functions synergistically with insulin and prevents diabetic nephropathy. However, the molecular mechanism of the synergistic effect of HOR and insulin needs to be elucidated.

Inhibition of hepatocyte nuclear factor 1b induces hepatic steatosis through DPP4/NOX1-mediated regulation of superoxide.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder that is closely associated with insulin resistance and type 2 diabetes. Previous studies have suggested that hepatocyte nuclear factor 1b (HNF1b) ameliorates insulin resistance. However, the role of HNF1b in the regulation of lipid metabolism and hepatic steatosis remains poorly understood. We found that HNF1b expression was decreased in steatotic livers. We injected mice with lentivirus (LV) expressing HNF1b shRNA to generate mice with hepatic knockdown of HNF1b. We also injected high fat (HF) diet-induced obese and db/db diabetic mice with LV expressing HNF1b to overexpress HNF1b. Knockdown of HNF1b increased hepatic lipid contents and induced insulin resistance in mice and in hepatocytes. Knockdown of HNF1b worsened HF diet-induced increases in hepatic lipid contents, liver injury and insulin resistance in mice and PA-induced lipid accumulation and impaired insulin signaling in hepatocytes. Moreover, overexpression of HNF1b alleviated HF diet-induced increases in hepatic lipid content and insulin resistance in mice. Knockdown of HNF1b increased expression of genes associated with lipogenensis and endoplasmic reticulum (ER) stress. DPP4 and NOX1 expression was increased by knockdown of HNF1b and HNF1b directly bound with the promoters of DPP4 and NOX1. Overexpression of DPP4 or NOX1 was associated with an increase in lipid droplets in hepatocytes and decreased expression of DPP4 or NOX1 suppressed the effects of knockdown of HNF1b knockdown on triglyceride (TG) formation and insulin signaling. Knockdown of HNF1b increased superoxide level and decreased glutathione content, which was inhibited by downregulation of DPP4 and NOX1. N-acetylcysteine (NAC) suppressed HNF1b knockdown-induced ER stress, TG formation and insulin resistance. Palmitic acid (PA) decreased HNF1b expression which was inhibited by NAC. Taken together, these studies demonstrate that HNF1b plays an essential role in controlling hepatic TG homeostasis and insulin sensitivity by regulating DPP4/NOX1mediated generation of superoxide.