Project Summary/Abstract Project 1 will generate and use mouse models for studying how exposure to hepatotoxic Superfund substances causes fatty liver disease and its different manifestations, including inflammation, fibrosis and cancer. It has become increasingly clear that exposure to many industrial and environmental toxicants can cause toxicant- associated fatty liver disease (TAFLD) and its more serious form, toxicant-associated steatohepatitis (TASH), whose pathological signs are strikingly similar to those of non-alcoholic fatty liver disease (NAFLD) and non- alcoholic stateohepatits (NASH), respectively. As the pathogenic mechanisms underlying to TAFLD and TASH are poorly understood, we posit that better insight to toxicant-induced liver diseases can be gained from studying them along with NAFLD and NASH. Moreover, pre-existing NAFLD can increase the susceptibility of the liver to toxicant induced damage, further justifying the study of this metabolic condition that can progress to NASH or TASH and then to liver cirrhosis and cancer, diseases whose incidence is greater in economically disadvantaged Indian- and Mexican-American populations. During the past project period we obtained exciting and important preliminary results according to which the development and clinical progression of NASH and TASH are strongly modulated by two different populations of B lymphocytres, spleen-derived B2 B cells that promote fibrotic progression and IgA-producing plasmocytes that attenuate the onset of liver fibrosis, but favor the establishment of an immunosuppressive microenvironment permissive to the growth and progression of hepatocellular carcinoma (HCC). Correspondingly, the specific targeting of IgA+ plasmocytes results in immune rejection of established HCC. To better understand the role of these B populations in the development and progression of NASH and TASH and to generate a new therapeutic approach to the treatment of toxicant-and obesity-induced liver cancer we will: 1) Define the pathways responsible for B cell recruitment into toxicant-damaged steatotic livers; 2) Determine how TASH and NASH trigger IgA class switch recombination (CSR) in liver-infiltrating B cells; 3) Determine how IgA+ plasmocytes attenuate NASH- and TASH-associated liver fibrosis; 4) Determine the role of T cell subsets and microbiota in the development of NASH and TASH; 5) identify secreted metabolites that along with IgA can be used for non-invasive detection of liver fibrosis; 6) determine the role of IgA+ plasmocytes in NASH and TASH progression to HCC. Our ability to accomplish these goals and gain a much better understanding of the immune mechanisms that affect the pathogenesis of NASH and TASH will be greatly enhanced by our research cores and the close collaborative interactions with other research projects.