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 #
5K08DK097178-02
Application #
8538971
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
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
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
Kakazu, Eiji; Mauer, Amy S; Yin, Meng et al. (2016) Hepatocytes release ceramide-enriched pro-inflammatory extracellular vesicles in an IRE1α-dependent manner. J Lipid Res 57:233-45
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; Krishnan, Anuradha et al. (2016) Lipid-Induced Signaling Causes Release of Inflammatory Extracellular Vesicles From Hepatocytes. Gastroenterology 150:956-67
Malhi, H; Loomba, R (2016) Editorial: dark chocolate may improve NAFLD and metabolic syndrome by reducing oxidative stress. Aliment Pharmacol Ther 44:533-4
Hirsova, Petra; Ibrabim, Samar H; Gores, Gregory J et al. (2016) Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis. J Lipid Res 57:1758-1770
Verma, Vikas K; Li, Haiyang; Wang, Ruisi et al. (2016) Alcohol stimulates macrophage activation through caspase-dependent hepatocyte derived release of CD40L containing extracellular vesicles. J Hepatol 64:651-60
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
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
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
Idrissova, Leila; Malhi, Harmeet; Werneburg, Nathan W et al. (2015) TRAIL receptor deletion in mice suppresses the inflammation of nutrient excess. J Hepatol 62:1156-63

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