Non-alcoholic fatty liver disease (NAFLD) is a growing metabolic disorder that is closely associated with
obesity and insulin resistance/type 2 diabetes. NAFLD begins with a simple hepatic steatosis, which in some
individuals may progress to nonalcoholic steatohepatitis (NASH), an advanced abnormity that may further lead
to fibrosis, cirrhosis, liver failure or cancer. Whereas enhanced de novo lipogenesis and fatty acid influx initiate
the hepatic steatosis, hepatic inflammation triggers the transition from hepatic steatosis to NASH and is an
important driving force of the pathological progression towards fibrogenesis. However, the exact mechanisms
underlying the development and progression of NAFLD remain poorly understood. While numerous studies
have been devoted to the evaluation of genetic factors involved in obesity and its associated complications such
as NAFLD, much is unknown about epigenetic changes in this process. Epigenetic regulation, including histone
acetylation, is a molecular link between environmental factors (e.g., diets) and complex diseases (e.g., NAFLD).
Histone deacetylase 1 (HDAC1) acts to remove acetyl groups from lysine residues in histones, thereby
inhibiting gene expression. Our preliminary data suggested that liver-specific deletion of HDAC1 decreased
hepatic lipid accumulation, inflammation and fibrosis in mice. Therefore, we hypothesize that HDAC1 plays a
central role in the development of NAFLD. Aim 1 will determine the role of HDAC1 in promoting hepatic
steatosis. We have generated genetic models with liver specific deletion or overexpression of HDAC1. We will
determine: 1) whether and how liver-specific deletion of HDAC1 prevents, whereas specific overexpression of
HDAC1 promotes hepatic steatosis in mice; 2) whether down-regulation of the transcriptional repressor KLF3
mediates the effect of HDAC1 in promoting hepatic lipid storage via regulation of PPARγ. Aim 2 will determine
the role of HDAC1 in promoting hepatic inflammation in the development of NASH. Hepatic inflammation triggers
the transition from hepatic steatosis to NASH. We will determine: 1) whether liver-specific deletion of HDAC1
prevents, whereas specific overexpression of HDAC1 promotes NASH in mice; 2) whether down-regulation of
the transcriptional repressor KLF3 mediates the effect of HDAC1 in promoting hepatic chemotaxis and
inflammation via regulation of C-Jun. Aim 3 will determine the mechanism underlying regulation of HDAC1 by
excess nutrients. O-GlcNAcylation has emerged as a key nutrient sensor that regulates cellular metabolic
pathways in response to over-nutritional cues. We will determine whether HDAC1 O-GlcNAcylation by excess
nutrients such as glucose and saturated fatty acids, levels of which are commonly elevated in obesity, increases
HDAC1 protein stability by preventing ubiquitination and proteasomal degradation, leading to enhanced HDAC1
protein content and activity. This project will define the role of HDAC1 as a nutrient sensor that regulates hepatic
lipid metabolism and inflammation in the development and progression of NFALD. Our studies could guide the
development of the epigenetic regulation as new therapeutic targets in the treatment of NAFLD.