Interrelationship between Liver X Receptor α, Sterol Regulatory Element-binding Protein-1c, Peroxisome Proliferator-activated Receptor γ, and Small Heterodimer Partner in the Transcriptional Regulation of Glucokinase Gene Expression in Liver

Abstract

Liver glucokinase (LGK) plays an essential role in controlling blood glucose levels and maintaining cellular metabolic functions. Expression of LGK is induced mainly regulated by insulin through sterol regulatory element-binding protein-1c (SREBP1c) as a mediator. Since LGK expression is known to be decreased in the liver of liver X receptor (LXR) knockout mice, we have investigated whether LGK might be directly activated by LXR␣. Furthermore, we have studied interrelationship between transcription factors that control gene expression of LGK. In the current studies, we demonstrated that LXR␣ increased LGK expression in primary hepatocytes and that there is a functional LXR response element in the LGK gene promoter as shown by electrophoretic mobility shift and chromatin precipitation assay. In addition, our studies demonstrate that LXR␣ and insulin activation of the LGK gene promoter occurs through a multifaceted indirect mechanism. LXR␣ increases SREBP-1c expression and then insulin stimulates the processing of the membrane-bound precursor SREBP-1c protein, and it activates LGK expression through SREBP sites in its promoter. LXR␣ also activates the LGK promoter by increasing the transcriptional activity and induction of peroxisome proliferator-activated receptor (PPAR)-␥, which also stimulates LGK expression through a peroxisome proliferator-responsive element. This activation is tempered through a negative mechanism, where a small heterodimer partner (SHP) decreases LGK gene expression by inhibiting the transcriptional activity of LXR␣ and PPAR␥ by directly interacting with their common heterodimer partner RXR␣. From these data, we propose a mechanism for LXR␣ in controlling the gene expression of LGK that involves activation through SREBP-1c and PPAR␥ and inhibition through SHP.

Liver X receptor α-mediated regulation of lipogenesis by core and NS5A proteins contributes to HCV-induced liver steatosis and HCV replication

“…There is experimental evidence that LXRa induces the expression of lipogenic genes involved in fatty acid synthesis. 19,20 In our study, HCV NS5A and core proteins induced intracellular total lipid and triglyceride accumulation by upregulating gene expression and the transcriptional activity of LXRa, and leading to an increased expression of its lipogenic target genes SREBP-1c, PPAR-g, and FAS. Interestingly, lipogenic capacity was significantly higher when NS5A protein was expressed.…”

“…LXRa forms heterodimers with the retinoid X receptor (RXR)a and activates SREBP-1c, PPAR-g, and FAS transcription by binding to the LXRE sequences in their promoters. 20,37,38 In turn, SREBP-1c activates genes involved in lipid and cholesterol metabolism, such as FAS, through binding to the SRE in the gene promoters. 38,39 In the current study, transcriptional regulation occurred via activation of the LXRE present in the promoter of lipogenic genes, thereby suggesting that the core and NS5A-mediated regulation of lipogenesis involves direct targeting of LXRa.…”

“…18 Peroxisome proliferator-activated receptor-g (PPAR-g) and sterol regulatory element-binding protein-1c (SREBP-1c) are two transcription factors activated by LXRa with an important role in regulating fatty acid synthesis. 19,20 Little is known, however, on the role of LXRa in the development of hepatic steatosis in HCV infection. We have recently shown that the LXRa gene and its lipogenic targets PPAR-g, SREBP-1c, SREBP-2, fatty acid synthase (FAS), and fatty acid translocase CD36 are overexpressed in the liver of HCV genotype 1 patients.…”

Activation of LXR increases acyl-CoA synthetase activity through direct regulation of ACSL3 in human placental trophoblast cells

“…Possible candidates are the known LXR target genes SREBP-1c ( 48 ) and carbohydrate responsive element binding protein ( 49 ), but peroxisome prolifertaor-activated receptor ␥ (PPAR ␥ ) and small heterodimer partner (SHP) could also be involved in this transcriptional regulation of ACSL3. A recent report demonstrated an interrelationship between LXR ␣ , SREBP-1c, PPAR ␥ , and SHP in the transcriptional regulation of glucokinase gene expression in liver ( 50 ).…”

RXR agonists inhibit high glucose-induced upregulation of inflammation by suppressing activation of the NADPH oxidase-nuclear factor-κB pathway in human endothelial cells

“…Retinoid X receptor (RXR) is a unique member of the nuclear hormone receptor superfamily as it forms heterodimers with many nuclear receptors such as peroxisome proliferator-activated receptor (PPAR) and liver X receptor (LXR), which play critical roles in regulating vascular functions and lipid metabolism (Kim et al, 2009). 9-cis-RA is a natural ligand for RXR and many synthetic compounds with selectivity for RXR have been developed (Dawson and Zhang, 2002).…”