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PPAR?-dependent Insig2a overexpression inhibits SREBP-1c processing during fasting.

ABSTRACT: Peroxisome-proliferator-activated receptor alpha (PPAR?) and sterol regulatory element-binding protein (SREBP) play a role in regulating cellular fatty acid and cholesterol homeostasis via fatty acid oxidation and lipogenesis. The control of SREBP processing is regulated by the insulin induced gene (INSIG)2a protein, which binds SREBP to prevent SREBP translocation to the Golgi apparatus during nutrient starvation in the liver. However, the regulation of SREBP-1c processing by INSIGs during fasting and the regulatory mechanisms of the mouse Insig2a gene expression have not been clearly addressed. In the present study, we found that Insig2a was upregulated by PPAR? in mouse livers and primary hepatocytes during fasting, whereas Insig2a mRNA expression was decreased in the livers of refed mice. A PPAR-responsive element between -126?bp and -114?bp in the Insig2a promoter was identified by a transient transfection assay and a chromatin immunoprecipitation assay; its role in regulation by PPAR? was characterised using Ppar?-null mice. These results suggest that PPAR? is a trans-acting factor that enhances Insig2a gene expression, thereby suppressing SREBP-1c processing during fasting.

SUBMITTER: Lee JH

PROVIDER: S-EPMC5577246 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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PPARα-dependent Insig2a overexpression inhibits SREBP-1c processing during fasting.

Lee Jae-Ho JH Kang Hye Suk HS Park Hyeon Young HY Moon Young-Ah YA Kang Yu Na YN Oh Byung-Chul BC Song Dae-Kyu DK Bae Jae-Hoon JH Im Seung-Soon SS

Scientific reports 20170830 1

Peroxisome-proliferator-activated receptor alpha (PPARα) and sterol regulatory element-binding protein (SREBP) play a role in regulating cellular fatty acid and cholesterol homeostasis via fatty acid oxidation and lipogenesis. The control of SREBP processing is regulated by the insulin induced gene (INSIG)2a protein, which binds SREBP to prevent SREBP translocation to the Golgi apparatus during nutrient starvation in the liver. However, the regulation of SREBP-1c processing by INSIGs during fast ...[more]

PMID: 28855656

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Project description:Salusin‑α and adiponectin, are vasoactive peptides with numerous similar biological effects related to lipid metabolism. Adiponectin has been shown to reduce fatty acid oxidation and to inhibit lipid synthesis of liver cells through its receptor, adiponectin receptor 2 (AdipoR2), but whether salusin‑α is able to interact with AdipoR2, was not previously reported. To investigate this, in vitro experiments were carried out. The overexpression and interference recombinant plasmids were constructed with salusin‑α. The lentiviral expression systems of salusin‑α overexpression and interference were respectively synthesized in 293T cells, and 293T cells were infected with the lentivirus. Finally, the association between salusin‑α and AdipoR2 was analyzed by semi‑quantitative PCR. Subsequently, HepG2 cells were also infected with these viruses. The expression levels of AdipoR2, peroxisome proliferator‑activated receptor‑α (PPARα), apolipoprotein A5 (ApoA5) and sterol regulatory element‑binding transcription factor 1 (SREBP‑1c) were detected by western blotting, and AdipoR2 inhibitor (thapsigargin) and agonist [4‑phenyl butyric acid (PBA)] were used to observe the resultant changes in the aforementioned molecules. The results obtained revealed that the overexpression of salusin‑α increased the level of AdipoR2 in 293T and HepG2 cells, led to an upregulation of the levels of PPARα and ApoA5, and inhibited the expression of SREBP‑1c, whereas the salusin‑α interference lentivirus exerted the opposite effects. Notably, thapsigargin inhibited the expression of AdipoR2, PPARα and ApoA5 in HepG2 cells of pHAGE‑Salusin‑α group, and caused an increase in the level of SREBP‑1c, whereas the opposite effects were observed in pLKO.1‑shSalusin‑α#1 group upon treatment with PBA. Taken together, these data demonstrated that overexpression of salusin‑α upregulated AdipoR2, which in turn activated the PPARα/ApoA5/SREBP‑1c signaling pathway to inhibit lipid synthesis in HepG2 cells, thereby providing theoretical data on which to base the clinical application of salusin‑α as a novel peptide for molecular intervention in fatty liver disease.

Dataset Information

PPAR?-dependent Insig2a overexpression inhibits SREBP-1c processing during fasting.

Publications

PPARα-dependent Insig2a overexpression inhibits SREBP-1c processing during fasting.

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