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Hilda Ghadieh Dissertation (PhD).pdf (7.7 MB)

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Impaired Hepatic Insulin Clearance Links Fatty Liver Disease to Atherosclerosis

Ghadieh, Hilda E.
http://rave.ohiolink.edu/etdc/view?acc_num=mco1533216686796754

Abstract Details

2018, Doctor of Philosophy (PhD), University of Toledo, Biomedical Sciences (Molecular Medicine).
Insulin resistance has long been considered to play a crucial role in the pathophysiology of metabolic syndrome that is the leading cause of mortality and morbidity worldwide. Metabolic diseases consist of a group of metabolic abnormalities that increase the risk of health problems, such as type 2 diabetes (T2D) and cardiovascular disease. Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and metabolic syndromes. It is the fastest growing cause of liver dysfunction. Its progressive form nonalcoholic steatohepatitis (NASH) is associated with hepatic fibrosis that can develop into cirrhosis. In addition, there is a growing body of evidence that among risk factors that promote atherosclerosis, metabolic syndrome is a potent predictor of cardiovascular events. Insulin resistance seems to play a major role in the pathophysiology of atherosclerosis in relation with metabolic syndrome. Given that patients with NAFLD/NASH are at a high risk to develop atherosclerosis; these two diseases may share some pathology. However, precise molecular mechanisms underlying the pathogenesis and progression of these diseases are not well understood. Thus studying the molecular link between them would pinpoint sites of more effective pharmacologic interventions. The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a protein that is markedly reduced in the liver of patients with NASH, promotes insulin clearance to regulate insulin action. Whether or not CEACAM1 links hyperinsulinemia to NAFLD/NASH and atherosclerosis still needs to be determined. CEACAM1 enhances the rate of uptake of the insulin-receptor complex into the clathrin-coated vesicles of hepatocytes. It also plays a major role in mediating the negative acute effect on fatty acid synthase (Fasn) activity. As such, CEACAM1 regulates insulin and lipid metabolism. Mice with global null mutation of CEACAM1 (Cc1–/–) display hyperinsulinemia resulting from impaired insulin clearance, insulin resistance, steatohepatitis, plaque-like lesions in aortae, and obesity. We herein are highlighting the specific role of hepatic CEACAM1 in regulating insulin and lipid metabolism, hepatic steatosis and altered energy balance. Moreover, liver-based rescuing of CEACAM1 resulted in full normalization of the metabolic phenotype. These data underscore the key role of CEACAM1-dependent hepatic insulin clearance pathways in regulating systemic insulin sensitivity, lipid homeostasis and energy balance. Furthermore, white adipose tissue-derived fatty acids repressed hepatic CEACAM1-dependent regulation of insulin and lipid metabolism and adenoviral-mediated CEACAM1 redelivery countered the adverse metabolic effect of the high-fat diet on insulin resistance, hepatic steatosis, visceral obesity and energy expenditure. These data assign a causative role for lipolysis-driven decrease in hepatic CEACAM1 levels. Furthermore, persistence of hyperinsulinaemia and insulin resistance in Cc1-/- mice after blocking lipolysis with nicotinic acid demonstrates that these metabolic abnormalities arise independent of visceral obesity and that they are the cause rather than the consequence of lipolysis. We show here that hepatic CEACAM1 deficiency, acting through hyperinsulinemia and systemic insulin resistance promotes a state of lipid-dependent vascular dysfunction, alters endothelial cell function, contributing to atherosclerosis development in a cell-nonautonomous fashion. In addition, we are showing that the cell autonomous metabolic and fibrogenic effect of specifically deleting CEACAM1 from hepatic stellate cells (HSC) leads to their activation. We also have identified a novel role of exenatide, a glucagon-like peptide-1 receptor agonist, on insulin clearance by inducing CEACAM1 expression in parallel to insulin secretion to prevent chronic hyperinsulinemia and subsequent increase in hepatic de novo lipogenesis and NAFLD. Exenatide also prevented diet-induced pro-fibrogenesis and hepatocellular injury in a CEACAM1-dependent mechanism. The physiologic implication of increased insulin extraction in the face of elevated insulin secretion by exenatide is to maintain homeostatic plasma insulin levels, an essential determinant of insulin sensitivity and lipid homeostasis. Hence, our studies demonstrate that the CEACAM1-dependent mechanism of hyperinsulinemia-induced insulin resistance plays a critical role in the development of NAFLD/NASH and atherosclerosis. This finding is of clinical importance because it suggests that the metabolic syndrome is not only a collection of abnormalities that should be considered and treated independently. A defect in insulin singling links those diseases since it acts on both glucose and cholesterol metabolisms. These data suggest that finding and curbing the molecular pathways that lead the insulin resistance associated with metabolic syndrome will add a new dimension to experimental therapeutics in this area.
Sonia Najjar, PhD (Committee Chair)
Guillermo Vazquez, PhD (Committee Member)
Jennifer Hill, PhD (Committee Member)
Rajesh Gupta, MD (Committee Member)
David Kennedy, PhD (Committee Member)
Steven Haller, PhD (Committee Member)
455 p.
Biomedical Research
CEACAM1; insulin clearance; hyperinsulinemia; insulin resistance; type 2 diabetes; obesity; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; atherosclerosis; cardiovascular disease; metabolic syndrome; energy balance

Recommended Citations

Citations

  • Ghadieh, H. E. (2018). Impaired Hepatic Insulin Clearance Links Fatty Liver Disease to Atherosclerosis [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1533216686796754

    APA Style (7th edition)

  • Ghadieh, Hilda. Impaired Hepatic Insulin Clearance Links Fatty Liver Disease to Atherosclerosis. 2018. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1533216686796754.

    MLA Style (8th edition)

  • Ghadieh, Hilda. "Impaired Hepatic Insulin Clearance Links Fatty Liver Disease to Atherosclerosis." Doctoral dissertation, University of Toledo, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=mco1533216686796754

    Chicago Manual of Style (17th edition)

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This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.