My long term career objective is to define the mechanisms of liver inflammation in nonalcoholic steatohepatitis. The current proposal focuses on the dichotomous role of two of the three known branches of the endoplasmic reticulum (ER) stress-activated unfolded protein response (UPR) in the regulation of macrophage biology in NASH. In preliminary experiments we have observed that macrophages are activated upon treatment with palmitic acid (PA);we have termed this phenomenon lipoactivation. Lipoactivated macrophages undergo ER stress, and also cell death, termed lipoapoptosis. We have observed macrophage accumulation in a mouse model of NASH along with elevated PA levels. Our preliminary observations have led to the central hypothesis that the UPR regulates either lipoactivation or lipoapoptosis in hepatic macrophages thereby instigating or mitigating inflammation, respectively, in steatohepatitis. Therefore, the goals of this proposal are to understand: i) how the Inositol Requiring Protein-1 alpha (IRE1?)/ X-box binding protein (XBP-1) branch of the UPR increases the proinflammatory milieu in the liver by enhancing macrophage activation and cytokine secretion via targeting the cytokines monocyte chemotactic protein-1 (MCP-1) and interleukin-1beta (IL-1?), and ii) how the CHOP branch of the UPR increases the antiinflammatory milieu in the liver by enhancing macrophage apoptosis by decreasing the antiapoptotic protein Mcl-1 and increasing the proapoptotic protein Bim. The proposed experiments will employ complementary in vitro and in vivo models of lipotoxicity and NASH, respectively;and chemical, pharmacological, molecular and genetic approaches to address the specific aims to test the hypotheses that: i) The UPR determines macrophage recruitment and activation via IRE1?/XBP-1 signalling, ii) ER stress via CHOP promotes macrophage apoptosis, and iii) The UPR regulates hepatic inflammation in NASH. To address these hypotheses the applicant has become adept at macrophage isolation, assays of cytokine secretion, transcriptional regulation, and in vivo rodent models of conditional deletion of IRE1? or CHOP. With funding through this K08 Mentored Clinical Scientist Research Career Development Award the applicant will pursue additional training in macrophage biology and Innate Immunology to develop expertise in these key regulators of hepatic inflammation. The applicant has established a network consisting of Dr. Gregory J. Gores as her primary mentor, Dr. Peter J. Wettstein as the Immunology collaborator, and Dr. Randal J. Kaufman as the UPR collaborator. Our results will yield mechanistic insights into regulation of macrophage lipoactivation and lipoapoptosis by individual UPR components, thus identifying potential molecules that can be targeted by therapeutic interventions.

Public Health Relevance

Liver involvement in obesity results in fatty liver, which can range from mild to severe inflammation of the liver. Due to increasing obesity, the number of people affected by fatty liver is increasing, and there are no good treatments for this disease. With the proposed research we will identify how inflammation is regulated in the liver, and thus, identify molecules that can potentially be targeted to treat this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08DK097178-01
Application #
8424378
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2012-09-01
Project End
2017-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$145,973
Indirect Cost
$10,813
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Camilleri, Michael; Malhi, Harmeet; Acosta, Andres (2017) Gastrointestinal Complications of Obesity. Gastroenterology 152:1656-1670
Maiers, Jessica L; Kostallari, Enis; Mushref, Malek et al. (2017) The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice. Hepatology 65:983-998
Yin, Meng; Glaser, Kevin J; Manduca, Armando et al. (2017) Distinguishing between Hepatic Inflammation and Fibrosis with MR Elastography. Radiology 284:694-705
Mauer, Amy S; Hirsova, Petra; Maiers, Jessica L et al. (2017) Inhibition of sphingosine 1-phosphate signaling ameliorates murine nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 312:G300-G313
Hirsova, Petra; Ibrahim, Samar H; Krishnan, Anuradha et al. (2016) Lipid-Induced Signaling Causes Release of Inflammatory Extracellular Vesicles From Hepatocytes. Gastroenterology 150:956-67
Ibrahim, Samar H; Hirsova, Petra; Tomita, Kyoko et al. (2016) Mixed lineage kinase 3 mediates release of C-X-C motif ligand 10-bearing chemotactic extracellular vesicles from lipotoxic hepatocytes. Hepatology 63:731-44
Hirsova, Petra; Ibrahim, Samar H; Verma, Vikas K et al. (2016) Extracellular vesicles in liver pathobiology: Small particles with big impact. Hepatology 64:2219-2233
Ibrahim, Samar H; Hirsova, Petra; Malhi, Harmeet et al. (2016) Animal Models of Nonalcoholic Steatohepatitis: Eat, Delete, and Inflame. Dig Dis Sci 61:1325-36
Malhi, Harmeet; Allen, Alina M; Watt, Kymberly D (2016) Nonalcoholic fatty liver: optimizing pretransplant selection and posttransplant care to maximize survival. Curr Opin Organ Transplant 21:99-106
Malhi, H; Loomba, R (2016) Editorial: dark chocolate may improve NAFLD and metabolic syndrome by reducing oxidative stress. Aliment Pharmacol Ther 44:533-4

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