Tissue Responses to Metabolic Stress

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 DESCRIPTION (provided by applicant): In non-alcoholic fatty liver disease (NAFLD), excess lipid accumulation can damage hepatic tissues leading to steatohepatitis or cirrhosis. Given the high prevalence of NAFLD and the serious consequences of liver dysfunction, understanding the pathogenesis of lipotoxicity in the liver is of high importance to human health. Our recent studies uncovered an unanticipated role for small nucleolar RNAs (snoRNAs) encoded in the rpL13a locus in the response of non-adipose tissues to lipid overload. These non-coding RNAs likely function by targeting 2ʹ′-O-methylations to specific cellular RNAs, although the precise targets of rpL13a snoRNAs in lipotoxic responses are not known. The first aim of this study will probe the mechanism of action of the rpL13a snoRNAs by using two complementary systems biology approaches to identify the targets of the snoRNAs in hepatocytes under lipotoxic conditions. The second aim of this study will leverage snoRNA loss-of-function murine models to analyze the physiological contributions of the rpL13a snoRNAs to diet-induced steatohepatitis.