Nonalcoholic fatty liver disease (NAFLD) is the fastest-growing cause of liver dysfunction, affecting more than 80 million Americans, and leading to nonalcoholic steatohepatitis (NASH) in nearly 10 million patients. The disease is a constellation of abnormal metabolism and liver histopathology, including: simple steatosis, steatohepatitis, cellular injury, and fibrosis. Its progressive form, NASH, is associated with hepatic fibrosis that can progress into cirrhosis. NAFLD is associated with obesity, metabolic syndrome and type 2 diabetes mellitus. Intrahepatic lipid accumulation is associated with increased lipolysis, VLDL-triglyceride secretion, and oxidative stress. CEACAM1, a transmembrane substrate of the insulin receptor, promotes hepatic insulin clearance and mediates a negative acute effect of insulin on fatty acid synthase activity, thus regulating insulin and lipid metabolism. NAFLD patients exhibit a marked reduction in their hepatic CEACAM1 levels, and the degree of the disease correlates with the extent of the loss of CEACAM1. Ceacam1 ablation in liver recapitulates faithfully all features of human NAFLD/NASH, including spontaneous chicken-wire fibrosis that is rarely observed in mice on C57BL/6 background. Activated hepatic stellate cells (HSC) is a major source of fibrosis. Because virtually all liver cells contribute to HSC activation, we set out to identify the main cellular sites for CEACAM1's regulation of fibrosis. Lipid accumulation in hepatocytes as well as excessive capillarization of the liver sinusoid can activate HSC. Preliminary data show: 1) reduced Ceacam1 mRNA in activated HSC from humans and CCl4-treated mice and 2) spontaneous hepatic fibrosis in AlbCre+Cc1fl/fl and VECad+Cc1fl/fl mice with liver-specific and endothelial cell-specific Ceacam1 deletion, respectively. Given the well-documented role of CEACAM1 in regulating lipid homeostasis in hepatocytes, and in maintaining vascular integrity, we hypothesized that CEACAM1 function along the stellate cell-endothelial cell axis is critical to the pathogenesis of hepatic fibrosis. To test this hypothesis, we propose in Aim 1 to examine the cell-autonomous metabolic and fibrogenic effect of deleting Ceacam1 from HSC to test whether CEACAM1's regulation of HSC activation and fibrosis is independent of its effect on insulin clearance and fatty acid synthesis in hepatocytes.
In Aim 2, we will examine the cell non-autonomous effect of deleting Ceacam1 from endothelial cells on HSC activation.
In Aim 3, we will investigate whether Ceacam1 induction mediates the therapeutic effect of PPAR? agonist, pioglitazone. The ultimate goal of this work is to identify CEACAM1-dependent pathways in the pathogenesis of fibrosis to develop appropriate therapeutic targets.
Fatty liver disease is the new epidemic. Uncontrolled, it progresses to nonalcoholic fatty liver disease (NASH). Fibrosis is an integral part of the progression to cirrhosis and the eventual need for liver transplantation. This proposal focuses on identifying a critical mechanism that leads to fibrosis. Completion of these studies will provide a unique tool to better understand how fibrosis develops. This will help us establish targeted strategies to prevent fibrosis and liver injury, and to stem the progression of this fast-growing metabolic disease.
|Huang, Lei; Liu, Jehnan; Zhang, Xiao-Ou et al. (2018) Inhibition of protein arginine methyltransferase 5 enhances hepatic mitochondrial biogenesis. J Biol Chem 293:10884-10894|
|Ghadieh, Hilda E; Muturi, Harrison T; Russo, Lucia et al. (2018) Exenatide induces carcinoembryonic antigen-related cell adhesion molecule 1 expression to prevent hepatic steatosis. Hepatol Commun 2:35-47|
|Villa-Pérez, Pablo; Merino, Beatriz; Fernández-Díaz, Cristina M et al. (2018) Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice. Metabolism 88:1-11|
|Ghanem, Simona S; Muturi, Harrison T; DeAngelis, Anthony M et al. (2017) Age-dependent insulin resistance in male mice with null deletion of the carcinoembryonic antigen-related cell adhesion molecule 2 gene. Diabetologia 60:1751-1760|
|Ghadieh, Hilda E; Muturi, Harrison T; Najjar, Sonia M (2017) Exenatide Prevents Diet-induced Hepatocellular Injury in A CEACAM1-Dependent Mechanism. J Diabetes Treat 2017:|
|Russo, Lucia; Muturi, Harrison T; Ghadieh, Hilda E et al. (2017) Liver-specific reconstitution of CEACAM1 reverses the metabolic abnormalities caused by its global deletion in male mice. Diabetologia 60:2463-2474|
|Heinrich, Garrett; Russo, Lucia; Castaneda, Tamara R et al. (2016) Leptin Resistance Contributes to Obesity in Mice with Null Mutation of Carcinoembryonic Antigen-related Cell Adhesion Molecule 1. J Biol Chem 291:11124-32|
|Ghanem, Simona S; Heinrich, Garrett; Lester, Sumona G et al. (2016) Increased Glucose-induced Secretion of Glucagon-like Peptide-1 in Mice Lacking the Carcinoembryonic Antigen-related Cell Adhesion Molecule 2 (CEACAM2). J Biol Chem 291:980-8|
|Ramakrishnan, Sadeesh K; Russo, Lucia; Ghanem, Simona S et al. (2016) Fenofibrate Decreases Insulin Clearance and Insulin Secretion to Maintain Insulin Sensitivity. J Biol Chem 291:23915-23924|
|Stechschulte, Lance A; Qiu, Bin; Warrier, Manya et al. (2016) FKBP51 Null Mice Are Resistant to Diet-Induced Obesity and the PPAR? Agonist Rosiglitazone. Endocrinology 157:3888-3900|
Showing the most recent 10 out of 47 publications