Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05
  • 2024-06
  • 2024-07
  • br Epigenetic regulation of genes

    2019-06-13


    Epigenetic regulation of genes involved in hepatic lipid metabolism by S1P and SHP The signaling cascade of CBA > S1PR2 > SphK2 > S1P > HDAC1/2 > increased hepatic gene expression can differentially up-regulate blocks of genes involved in the hepatic metabolism of sterols and lipids (Fig. 3, Table 1). Therefore, how are bile acid-induced genes repressed after feeding? There are four main mechanisms that down-regulate expression of hepatic genes induced by bile acids. The first mechanism is an increase in the serum levels of fibroblast growth factor-15/19 that is induced in the intestines by bile acids via an FXR-dependent mechanism. Fibroblast growth factor-15/19 is known to down-regulate expression of cholesterol 7α-hydroxylase and bile-acid synthesis by activating specific cell signaling pathways in the liver. The second mechanism is CBA sequestration in the gallbladder that quenches bile-acid signaling in the intestines and liver. The third mechanism is reduction of insulin secretion as glucose is metabolized. The fourth mechanism is epigenetic repression by SHP-dependent mechanisms. In this regard, SHP is a NR without a DNA binding domain, and is synthesized in response to bile-acid activation of FXR. SHP interacts with known transcription factors (hepatocyte nuclear factor 4α, sterol regulatory element-binding protein 2, liver receptor homolog-1 and others), allowing repression of expression of numerous hepatic genes involved in nutrient metabolism. Moreover, it has been reported that SHP is activated post-translationally by phosphorylation (Thr-55) by PKCζ and then methylation (Arg-57) by protein arginine methyltransferase 5, which allows SHP to interact with the proteins that regulate gene repression. SHP activation has been demonstrated to interact with HDAC1/2, G9A histone lysine methyltransferase, and chromatin-remodeling enzymes in the nucleus that promote gene repression. Therefore, nuclear S1P and activated SHP may act together as a “biologic rheostat” to regulate expression of the hepatic genes involved in nutrient metabolism during the feed/fast pkg inhibitor (Fig. 3). The activation of cell signaling pathways and SphK2 by TCA occurs very rapidly (minutes). In contrast, induction of SHP mRNA by TCA in chronic bile fistulae in rats occurs ≤3 h after TCA infusion. Therefore, SHP induction may be timed to repress gene expression after hepatic nutrient metabolism in the feed/fast cycle.
    Bile acids as cell-signaling molecules, SphK2 and fatty liver disease A HFD is associated with obesity and nonalcoholic fatty liver disease (NAFLD), which is a precursor of NASH and liver cancer. Cell signaling by bile pkg inhibitor acids and SphK2 may play important parts in NAFLD. In this regard, feeding S1PR2−/− or SphK2−/− mice a HFD for 2 weeks resulted in rapid accumulation of lipids in the liver. Recent studies by Lee et al. reported that SphK2 is induced by activation of the unfolded protein response (UPR) in mouse livers. These investigators demonstrated that ATF4 (a transcription factor induced by the UPR) is responsible for the up-regulation of expression of SphK2 mRNA. A HFD can induce endoplasmic reticulum stress and activate the UPR. These investigators over-expressed SphK2 using a recombinant adenovirus in mice fed a HFD. They found that, in animals over-expressing SphK2, there was a marked induction of genes encoding enzymes involved in β-oxidation of fatty acids and a significant decrease in hepatic levels of triglycerides and cholesterol. Moreover, over-expression of SphK2 increased AKTS473 phosphorylation significantly and improved tolerance to glucose and insulin without altering insulin secretion. CBAs may help regulate the metabolism of lipids, sterols and glucose by up-regulation of SphK2 expression (Fig. 4). It is not known if insulin up-regulates hepatic expression of SphK2. The signaling cascade of CBAs > S1PR2 > SphK2 > S1P > hepatic gene expression may be important in the prevention of accumulation of sterols and fats in the livers of animals on a HFD. However, pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6) may quench bile acid-activated cell signaling pathways and dysregulate the hepatic metabolism of glucose, sterols and lipids. For example, pro-inflammatory cytokines that activate the JNK1/2 signaling pathway are known to increase phosphorylation of insulin receptor substrate 2 and decrease the strength of insulin signaling. The activation of the insulin signaling pathway is important for FXR activation and SHP induction, which are key regulators of the hepatic metabolism of sterols and lipids. Hence, inflammation may be a key factor in the disruption of cell signaling pathways in the liver, and lead to fatty liver and an increased risk of NASH, cirrhosis and liver cancer.