Central Role of Estrogen-related receptor alpha in hepatic metabolism, non-alcoholic fatty  liver disease and aging  

Presenting author: Brijesh K. Singh

Estrogen-related receptor alpha (ESRRA/ERRα) is a member of the nuclear hormone  receptor superfamily. Unlike many other nuclear hormone receptors, ESRRA is an “orphan”  receptor since there is no endogenous or pharmacological ligand for ESRRA. We previously  showed that thyroid hormone stimulated hepatic β-oxidation by inducing autophagy as well  as mitochondrial activity and turnover by increasing ESRRA expression. Using various NASH  mouse models and aged livers, we observed that there was down-regulation of hepatic  ESRRA expression and lysosome-autophagy pathway. To better understand this potential  relationship between ESRRA and lysosome, we performed an unbiased proteomics analysis  of hepatic cells under starvation, a physiological process inducing lysosome-autophagy  pathway, where we identified ESRRA-PPARGC1A axis is associated with the mitochondria  and lysosome proteins and related pathways. We further examined liver tissues and the  hepatic transcriptomes from NAFLD patients and a several NAFLD mouse models, and found  that there was concurrent downregulation of ESRRA and lysosome-autophagy gene as well  as proteins expression. Later we further confirmed this in the livers collected from global  and liver-specific ESRRA knockout mice. In contrast, overexpression of ESRRA in mice livers led to increased autophagy and lysosomal activity. Moreover, analysing livers from aged  mice or senescent hepatic cells also showed similar signature. Additionally, molecular and  metabolomic phenotyping of the liver tissues from young ESRRA knockout mice and aged  livers showed signatures associated with NAFLD, insulin resistance and aging. While  overexpressing ESRRA in senescent cells restored lysosomal proteins. In summary, our  findings demonstrate that decreased ESRRA-lysosomal pathway plays a critical role in  NAFLD development and aging, and thus ESSRA itself may be a potential therapeutic target  for the treatment of NASH.