Role of ceacam1 and shp1 in the regulation of insulin sensitivity and hepatic glucose and lipid metabolism
|Authors:||Xu, Elaine Meng|
|Abstract:||Obesity and type 2 diabetes mellitus (T2D) are tightly associated with a common link, insulin resistance, a metabolic disorder developed from defective insulin action involving impaired insulin signaling and clearance. To investigate the pathogenesis of insulin resistance, many molecules modulating its signaling pathways as well as insulin receptor-mediated insulin clearance have been studied, including the protein tyrosine phosphatase (PTP) SHP1 and its regulated downstream molecule carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1 or CC1). CC1 in multiple isoforms contributes differentially to various cellular functions, the tyrosine (Tyr)-phosphorylated isoform of CC1 (CC1-L) is known to play an essential metabolic role in the hepatic regulation of insulin clearance and insulin-mediated acute inhibition of fatty acid synthase (FAS) activity. We have found that CC1-deficient (Cc1-/-) mice on standard diet (SD) already develop spontaneous hepatic steatosis with significantly elevated accretion of triglyceride (TG), total and esterified cholesterol. When challenged with a 55% kcal high-fat diet (HFD), these mice show greater susceptibility to the development of diet-induced hepatic steatosis and dysfunction, indicated by higher hepatic lipid content and serum levels of hepatic enzymes as markers of liver damage. Hepatic steatosis in the Cc1-/- mice is linked to a significant increase of key lipogenic (FAS, ACC) and cholesterol synthetic (HMGCR) enzymes, which is a result of increased nuclear activity of their positive gene transcription factors Srebp1c and Srebp2. Compared to their wild-type (WT) littermate controls, Cc1-/- mice exhibited impaired insulin clearance, glucose intolerance, liver insulin resistance, and elevated hepatic key gluconeogenic transcriptional activators Pgc1 and FoxO1. Lack of CC1 also exacerbated the HFD-induced glucose intolerance and hepatic insulin resistance, while insulin clearance was not further deteriorated. These data demonstrate that CC1 is a key regulator of hepatic lipogenesis and that Cc1-/- mice are predisposed to liver steatosis, leading to hepatic insulin resistance and liver damage, particularly when chronically exposed to dietary fat. An important Tyr phosphatase of CC1, SHP1, has been found previously by our lab to regulate glucose homeostasis and liver insulin clearance, but its potential implication in obesity-linked insulin resistance and hepatic steatosis has not yet been examined. We hereby report that SHP1 expression is significantly upregulated in metabolic tissues of HFD-fed obese mice. We have also further investigated the role of hepatocyte SHP1 in promoting insulin resistance and hepatic steatosis by generating hepatocyte-specific SHP1 knockout mice (Ptpn6H-KO). Upon HFD feeding, Ptpn6H-KO mice develop obesity as their Ptpn6f/f littermates. With consistently improved fasting glycemia, these mice are protected from obesity-induced liver insulin resistance as revealed by normalized insulin suppression of hepatic glucose production and hepatic insulin signaling with improved activation of insulin receptor and downstream signaling through Akt. More rapid insulin clearance in Ptpn6H-KO mice due to heightened CC1 tyrosine phosphorylation is also a possible contribution to the improved insulin action. Unexpectedly, obese Ptpn6H-KO mice exhibit enhanced hepatic steatosis. In detailed mechanisms, this is a result of 1) augmented hepatic lipogenesis, marked by upregulated activity and expression of SREBP-1 as well as the downstream regulated lipogenic enzymes such as FAS and ACC, 2) increased postprandial fatty acid uptake, possibly linked to the upregulation of PPAR gene expression and nuclear activity, and 3) decreased postprandial TG output in apolipoprotein B (ApoB)-associated lipoprotein particles, i.e. very low density lipoprotein (VLDL). More interestingly, the steatotic livers of these Ptpn6H-KO mice display comparable or even reduced level of inflammation accompanied by significantly less hepatocellular damage than that in their Ptpn6f/f counterparts. These results present hepatocyte SHP1 as a novel mediator of insulin resistance compromising hepatic glucose metabolism in diet-induced obesity. The enhanced diet-induced hepatic steatosis in Ptpn6H-KO mice provides a new role for SHP1 in liver lipid metabolism and further supports the bifurcation of insulin signaling in the regulation of hepatic glucose and lipid homeostasis or also confirms a possible disconnection between hepatic regulation of glucose and lipid metabolism. Although both CC1 and SHP1 are found in the same complex with Cdk2 and insulin receptor to regulate insulin clearance, they play opposing roles as CC1 is the positive regulator and SHP1 being the negative one. This is in accordance with the hepatic glucoregulation of insulin signaling for both molecules, since Cc1-/- mice show impaired glucose metabolism and insulin signaling whereas Ptpn6H-KO mice exhibit improvement. Interestingly, our observation of hepatic steatosis in both animal models, though with different characteristics, suggests that both CC1 and SHP1 limit hepatic lipid synthesis and storage, dependent or independent of insulin signaling. Findings from these studies using animal models lacking CC1 and SHP1 reveal complex and differential regulatory mechanisms of hepatic glucose and lipid metabolism, and they also provide important understanding of the hepatic regulation of insulin action and clearance.|
|Document Type:||Thèse de doctorat|
|Open Access Date:||19 April 2018|
|Collection:||Thèses et mémoires|
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