About one third of adults in the United States are diagnosed with fatty liver disease. About 10% will proceed to develop nonalcoholic steatohepatitis (NASH), and associated co-morbidities. Thus, it is imperative to understand the pathophysiology of the disease. NASH pathogenesis is currently explained on the basis of the """"""""two-hit"""""""" hypothesis, in which hepatic steatosis develops initially (first hit) and predisposes to lipid peroxidation and inflammation, leading to hepatitis, apoptosis, fibrosis and ultimately, cirrhosis (second hit). Association between the disease and insulin resistance has been disputed, largely because of the lack of a replicate animal model. We describe a novel mechanism linking NASH pathogenesis to the Carcino-Embryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1), a protein that regulates insulin sensitivity by mediating hepatic insulin clearance. It also acts as an anti-inflammatory signaling molecule. Liver-specific inactivation of CEACAM1 causes insulin resistance, visceral obesity and increased triglyceride production and output from liver. In preliminary data, we show that: (i) CEACAM1 levels are reduced in humans with visceral obesity;(ii) dominant-negative inhibition of CEACAM1 in transgenic mice yields a NASH-like syndrome under conditions that trigger inflammation, such as high-fat diet;while (iii) overexpression of CEACAM1 in liver of transgenic mice prevents insulin resistance and visceral obesity in response to high fat diet. We hypothesize that reduction in hepatic CEACAM1 constitutes a key mechanism in NASH development. To test this hypothesis, we propose to investigate whether liver-specific null mutation of CEACAM1 causes insulin resistance (Aim 1) and predisposes to NASH in response to high-fat diet (Aim 2).
In Aim 2, we will also seek to identify the signaling pathways responsible for NASH development by studying mice with hepatic Ceacam1 loss- and gain-of-function. We will examine whether CEACAM1 restoration in NASH models reverses hepatic insulin resistance, inflammation, lipid peroxidation and fibrosis.
In Aim 3, we will investigate the molecular target(s) and effector(s) of CEACAM1 responsible for NASH development. Based on a novel hypothesis, we will test the role of Mitochondrial Triglyceride Transfer Protein (MTP) in this process. The results of these experiments will define novel mechanisms linking insulin resistance with hepatic macrosteatosis, inflammation and cell injury associated with NASH. They will also identify CEACAM1 as a molecular biomarker of NASH as well as a potential target for its prevention and treatment.

Public Health Relevance

The incidence of Nonalcoholic Steatohepatitis (NASH) is expected to rise in parallel to the obesity epidemic. Because NASH frequently progresses to liver cirrhosis, and is becoming the leading cause of liver transplant in the US, it is imperative to understand its mechanisms. The disease is characterized by hepatic macrosteatosis, inflammation and fibrosis. It is frequently associated with other common metabolic abnormalities, such as insulin resistance, visceral obesity and liver steatosis, but the role of insulin resistance in the pathogenesis of NASH has been disputed, largely owing to the lack of a suitable animal model. We propose a novel mechanism of NASH, linked to the Carcino-Embryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1), a protein the inactivation of which causes insulin resistance, dyslipidemia, liver steatosis and inflammation. The proposal seeks to test the hypothesis that reduction in hepatic CEACAM1 constitutes an early mechanism in NASH development. The results of these experiments will define novel mechanisms linking insulin resistance and hepatic macrosteatosis, inflammation and cell injury associated with NASH. This will identify reduction in hepatic CEACAM1 as a molecular biomarker of NASH as well as a potential target for its prevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083850-02
Application #
7943014
Study Section
Special Emphasis Panel (ZRG1-EMNR-A (02))
Program Officer
Doo, Edward
Project Start
2009-09-30
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$374,500
Indirect Cost
Name
University of Toledo
Department
Physiology
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
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
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
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

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