Global Tudor‐SN transgenic mice are protected from obesity‐induced hepatic steatosis and insulin resistance

Abstract

In the current study, we explored the impact of Tudor‐staphylococcal nuclease (SN) on obesity induced by a high‐fat diet (HFD) in mice, because the functional involvement of Tudor‐SN in lipid metabolism in vivo is unknown. HFD‐transgenic (Tg) mice exhibited reductions in hepatic steatosis and systemic insulin resistance. There was no difference in hepatic lipid accumulation between chow‐fed wild‐type (WT) and chow‐fed Tg mice; consistently, no difference in activation of the lipogenic pathway was detected. Overactivation of hepatic nuclear sterol regulatory element‐binding protein (nSrebp2)‐2, the central regulator of cholesterol metabolic proteins, was observed in HFD‐Tg livers along with improved cholesterol homeostasis, but no such changes were observed in HFD‐WT livers. Consistent results were observed in vitro in α‐mouse liver 12 cells treated with palmitate mimicking the HFD state. In addition, global gene analysis indicated that various downstream targets of nSrebp2, were up‐regulated in HFD‐Tg livers. Moreover, HFD‐WT mice displayed islet hypertrophy and suppression of glucose‐induced insulin secretion from islets, whereas HFD‐Tg mice had normal pancreatic islets. This finding suggests that the improved pancreatic metabolism of HFD‐Tg mice is related to the systemic effect of insulin resistance, not to the autonomous influence of pancreatic cells. Tudor‐SN is likely to be a key regulator for ameliorating HFD‐induced hepatic steatosis and systemic insulin resistance in vivo.—Wang, X., Xin, L., Duan, Z., Zuo, Z., Wang, Y., Ren, Y., Zhang, W., Sun, X., Liu, X., Ge, L., Yang, X., Yao, Z., Yang, J. Global Tudor‐SN transgenic mice are protected from obesity‐induced hepatic steatosis and insulin resistance. FASEB J. 33, 3731–3745 (2019). http://www.fasebj.org

Effect of the Hepatocyte-Specific Deletion of SND1 in Mice on the Liver Insulin Resistance and Acute Liver Failure

“…SND1 protein was reported to promote the secretion of lipoprotein phospholipids in primary hepatocytes of rats [19,20]. Very recently, we also observed the reduced accumulation of triglyceride and the improved fatty liver and insulin resistance in the liver tissue of global SND1 transgenic mice under the treatment of a high-fat diet [14]. In this study, we are thus very interested in investigating further whether hepatocyte-speci c deletion of SND1 in mice affects the presence of insulin resistance induced by a high-fat diet.…”

“…At the 4 w, 8 w and 12 w of chow or high-fat diet in mice, a glucose tolerance test (GTT) was performed previously described [14]. Brie y, after the fasting treatment for 16 h, the mice were injected intraperitoneally by a glucose solution (1.5 g/kg).…”

“…The blood glucose levels were then measured at 0 min, 15 min, 30 min, 60 min, 90 min, and 120 min, respectively. In addition, we also performed the insulin tolerance test (ITT) [14] at the 16 w of chow or high-fat diet in mice. Brie y, 0.75 U/kg insulin (I8040, solarbio) was injected intraperitoneally in mice.…”

“…An acute insulin response assay was performed as previously described [14]. Brie y, at 24 w of chow or high-fat diet in mice, SND1 WT and LKO mice were fasted overnight, and anesthetized by intraperitoneal injection of 7% chloral hydrate (25 mg/g).…”

“…[3][4][5][6][7][8][9][10][11][12]. With regards to the SND1 expression-associated animal models, only global SND1 transgenic mice and hepatocyte-speci c SND1 transgenic mice (Alb/SND1 mice) [13] were reported [14]. Herein, we rst generated mice with the hepatocyte-speci c deletion of SND1 in the liver, namely an SND1 liver conditional knockout mice model, and investigated the role of SND1 in vivo in the issues of liver Insulin resistance and acute liver failure (ALF).…”