Abstract
Hepatocytes are the major cell-type in the liver responsible for the coordination of metabolism in response to multiple signaling inputs. Coordination occurs primarily at the level of gene expression via transcriptional networks composed of transcription factors, in particular nuclear receptors (NRs), and associated co-regulators, including chromatin-modifying complexes. Disturbance of these networks by genetic, environmental or nutritional factors can lead to metabolic dysregulation and has been linked to the progression of non-alcoholic fatty liver disease (NAFLD) toward steatohepatitis and even liver cancer. Since there are currently no approved therapies, major efforts are dedicated to identify the critical factors that can be employed for drug development. Amongst the identified factors with clinical significance are currently lipid-sensing NRs including PPARs, LXRs, and FXR. However, major obstacles of NR-targeting are the undesired side effects associated with the genome-wide NR activities in multiple cell-types. Thus, of particular interest are co-regulators that determine NR activities, context-selectivity, and associated chromatin states. Current research on the role of co-regulators in hepatocytes is still premature due to the large number of candidates, the limited number of available mouse models, and the technical challenges in studying their chromatin occupancy. As a result, how NR-co-regulator networks in hepatocytes are coordinated by extracellular signals, and how NR-pathway selectivity is achieved, remains currently poorly understood. We will here review a notable exception, namely a fundamental transcriptional co-repressor complex that during the past decade has become the probably most-studied and best-understood physiological relevant co-regulator in hepatocytes. This multiprotein complex contains the core subunits HDAC3, NCOR, SMRT, TBL1, TBLR1, and GPS2 and is referred to as the “NR-co-repressor complex.” We will particularly discuss recent advances in characterizing hepatocyte-specific loss-of-function mouse models and in applying genome-wide sequencing approaches including ChIP-seq. Both have been instrumental to uncover the role of each of the subunits under physiological conditions and in disease models, but they also revealed insights into the NR target range and genomic mechanisms of action of the co-repressor complex. We will integrate a discussion of translational aspects about the role of the complex in NAFLD pathways and in particular about the hypothesis that patient-specific alterations of specific subunits may determine NAFLD susceptibility and the therapeutic outcomes of NR-directed treatments.
Highlights
The liver is composed of multiple cell types, mainly hepatocytes and immune cells, and it is the major organ of glucose and lipid metabolism [1]
The hepatosteatosis phenotype observed upon hepatocyte-specific Nuclear receptor co-repressor (NCOR) depletion in NCOR Liver/hepatocyte-specific knockout (LKO) mice is in contrast to the normal hepatic lipid content despite modest increased lipogenesis in mutant NCOR Receptor-interacting domain (RID) or deacetylase-activating domain (DAD) knockin mouse models [18, 19, 22,23,24, 34]. These findings suggest that both interactions with nuclear receptor (NR) and enzymatic histone deacetylase 3 (HDAC3) activation contribute to, but are not absolutely required for, NCOR function in vivo
In line with the co-regulator exchange function, Transducin β-like protein 1 (TBL1)/Transducin β-like protein-related 1 (TBLR1) deficiency triggered the release of known Nuclear receptor Peroxisome proliferator-activated receptor alpha (PPARα) co-activators and promoted the recruitment of NCOR and HDAC3 to the promoters of fatty acid oxidation genes [42]
Summary
The liver is composed of multiple cell types, mainly hepatocytes and immune cells, and it is the major organ of glucose and lipid metabolism [1]. HDAC3 depletion in liver significantly increased de novo lipogenesis and cholesterol synthesis, but decreased fatty acid oxidation, causing dramatically elevated hepatic and serum triglyceride and cholesterol levels, resulting in severe hepatosteatosis [36, 38] (Figure 3B).
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