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 2??-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.
Non-alcoholic fatty liver disease (NAFLD) is a common complication of obesity and diabetes that can lead to serious liver dysfunction; however, it is not known precisely how excess fats cause liver damage. Our laboratory has recently identified small RNAs that mediate the toxicity of excess lipids in non-adipose cells. In this study, we will elucidate the mechanisms through which these small RNAs function in liver cells, and we will test whether these RNAs contribute to liver dysfunction in a mouse model of NAFLD. Our study could lead to new therapeutic targets for prevention of liver disease in obesity and diabetes.
| Rimer, Jamie M; Lee, Jiyeon; Holley, Christopher L et al. (2018) Long-range function of secreted small nucleolar RNAs that direct 2'-O-methylation. J Biol Chem 293:13284-13296 |
| Goldberg, Ira J; Reue, Karen; Abumrad, Nada A et al. (2018) Deciphering the Role of Lipid Droplets in Cardiovascular Disease: A Report From the 2017 National Heart, Lung, and Blood Institute Workshop. Circulation 138:305-315 |
| McCommis, Kyle S; Hodges, Wesley T; Brunt, Elizabeth M et al. (2017) Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis. Hepatology 65:1543-1556 |
| Caputa, George; Schaffer, Jean E (2016) RNA Regulation of Lipotoxicity and Metabolic Stress. Diabetes 65:1816-23 |
