In vivo hepatocyte implantation studies further confirm that H19 promoted hepatic steatosis by up-regulating both mTORC1 signalling axis and MLXIPL transcriptional network.
Carbohydrate response element binding protein (ChREBP) is a key transcriptional regulator of de novo lipogenesis (DNL) in response to carbohydrates and in hepatic steatosis.
It inhibited the activation of sterol regulatory element-binding proteins (1c and 2) and carbohydrate-responsive element-binding protein, and thus decreased steatosis as observed in T2D rats.
It was demonstrated that ChREBP induced FASN ChREBP‑ChoRE binding to accelerate the expression of FASN, leading to hepatocellular steatosis by facilitating H3 and H4 acetylation, H3K4 trimethylation and the phosphorylation of H3S10, but inhibiting the trimethylation of H3K9 and H4K20 in FASN promoter regions of HepG2 and L02 cells.
Furthermore, hepatic over-expression of lipogenic transcription factor ChREBP, but not SREBP-1c, in the liver of Bmal1-LKO mice also increases fatty acid oxidation and partially reduces ethanol-induced fatty liver and liver injury.
In WT mice, a high-fructose diet (HFrD) activated hepatic lipogenesis in a ChREBP-dependent manner; however, in Chrebp-KO mice, a HFrD induced steatohepatitis.
Pharmacological inhibition of liver RetSat may represent a therapeutic approach for steatosis.Fatty liver is one of the major features of metabolic syndrome and its development is associated with deregulation of systemic lipid and glucose homeostasis.Here Heidenreich et al. show that retinol saturase is implicated in hepatic lipid metabolism by regulating the activity of the transcription factor ChREBP.
Diet-induced obesity increases basal expression of ChREBPβ, which may increase the risk of developing hepatic steatosis, and fructose-induced activation is independent of gluconeogenesis.
Furthermore, we have shown a high complex carbohydrate diet selectively increases hepatic ChREBPβ expression, which associates with hepatic steatosis but not insulin resistance.
Here, the hypothesis is proposed that high-carbohydrate diets contribute to the association between hepatic steatosis and insulin resistance through activation of the transcription factor ChREBP (Carbohydrate response element binding protein).
Finally, ChREBP expression in liver biopsies from patients with nonalcoholic steatohepatitis was increased when steatosis was greater than 50% and decreased in the presence of severe insulin resistance.
We have previously reported that liver-specific inhibition of ChREBP prevents hepatic steatosis in ob/ob mice by specifically decreasing lipogenic rates in vivo.
Finally, in mouse models of type 2 diabetes and obesity, low SIK2 activity was associated with increased p300 HAT activity, ChREBP hyperacetylation, and hepatic steatosis.
We conclude that steatosis in HNF1alpha-mutated HCA results mainly from an aberrant promotion of lipogenesis that is linked to HNF1alpha inactivation and that is independent of both SREBP-1 and ChREBP activation.