FATTY LIVER DISEASE AFFECTS HALF OF ALL DAIRY CATTLE THAT HAVE RECENTLY GIVEN BIRTH. DESPITE RESEARCH INTO THE CAUSES AND SYMPTOMS OF FATTY LIVER DISEASE IN DAIRY CATTLE, INCIDENCE RATES REMAIN HIGH (COSTING FARMERS IN EXCESS OF $60 MILLION USD ANNUALLY) INDICATING THAT ON-FARM MANAGEMENT STRATEGIES ARE NOT ENOUGH TO PREVENT FATTY LIVER DISEASE. FURTHER UNDERSTANDING OF THE BIOCHEMICAL MECHANISMS THAT LEAD TO THE DEVELOPMENT OF FATTY LIVER IS NEEDED.RODENT RESEARCH HAS INDICATED THAT A KEY COORDINATOR OF METABOLISM IN THE LIVER IS DYSREGULATED IN CASES OF FATTY LIVER. BECAUSE CONTROL OF UTILIZATION OF NUTRIENTS IS CRITICAL TO THE SURVIVAL OF AN ORGANISM, THESE PROCESSES ARE CONSERVED THROUGHOUT EVOLUTION. WE, THEREFORE, EXPECT DAIRY CATTLE TO HAVE A SIMILAR DYSFUNCTION IN CASES OF FATTY LIVER.THE OVERARCHING HYPOTHESIS FOR THIS PROJECT IS, THEREFORE, THAT THIS KEY ENZYME (PHOSPHODIESTERASE 4B (PDE4B)) IS NOT REGULATED CORRECTLY IN THE LIVER OF CATTLE WHO ARE AFFECTED BY FATTY LIVER DISEASE AFTER CALVING. TO TEST THIS HYPOTHESIS, WE WILL UTILIZE OVER-CONDITIONED (OBESE) DAIRY CATTLE AND DAIRY CATTLE OF NORMAL BODY WEIGHT. WE WILL COLLECT TISSUE SAMPLES FROM HEALTHY LIVE ANIMALS AND LIVE ANIMALS THAT ARE EXPERIENCING FATTY LIVER DISEASE. USING THESE TISSUES, WE WILL DETERMINE WHICH OF THESE KEY COORDINATORS OF ENERGY USAGE IN THE LIVER ARE DYSREGULATED. SECOND, BASED ON THE FINDINGS FROM THE ON-FARM ANIMAL EXPERIMENT, WE WILL UTILIZE THE MODEL OF FATTY LIVER DISEASE DEVELOPED IN OUR LABORATORY THAT TAKES ADVANTAGE OF TISSUE COLLECTED FROM THE SLAUGHTERHOUSE. BY USING OUR LABORATORY DISEASE MODEL, WE WILL BE ABLE TO TEST ALREADY COMMERCIALLY AVAILABLE TREATMENTS FOR EFFICACY IN ALTERING THE ACTIVITY OF THESE ENZYMES AND FIXING THE DYSREGULATION. THE ULTIMATE GOAL OF THIS RESEARCH IS PREVENTING THE DEVELOPMENT OF FATTY LIVER DISEASE. BECAUSE COMMERCIALLY AVAILABLE DRUGS EXIST, WE ANTICIPATE THAT UPON IDENTIFICATION OF THE DYSREGULATED ENZYME, WE CAN ULTIMATELY DEVELOP AN ECONOMICAL TREATMENT TO BE USED ON THE FARM FOR PREVENTION OF FATTY LIVER DISEASE, THEREBY IMPROVING ANIMAL WELFARE AND SUSTAINABILITY FOR DAIRY FARMERS.