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

Area of Science:

• Metabolism
• Molecular Biology
• Gene Regulation

Background:

• Cellular fatty acid and cholesterol homeostasis are regulated by peroxisome-proliferator-activated receptor alpha (PPARα) and sterol regulatory element-binding protein (SREBP).
• Insulin induced gene 2a (INSIG2a) protein controls SREBP processing by preventing its translocation during nutrient starvation.
• Mechanisms regulating SREBP-1c processing by INSIGs during fasting and mouse Insig2a gene expression remain unclear.

Purpose of the Study:

• To investigate the regulatory mechanisms of mouse Insig2a gene expression during fasting.
• To elucidate the role of PPARα in regulating Insig2a expression and its impact on SREBP-1c processing.

Main Methods:

• Analysis of Insig2a mRNA expression in mouse livers and primary hepatocytes during fasting and refeeding.
• Identification of a PPAR-responsive element in the Insig2a promoter using transient transfection and chromatin immunoprecipitation assays.
• Characterization of PPARα's regulatory role using Pparα-null mice.

Main Results:

• Insig2a was upregulated by PPARα in mouse livers and primary hepatocytes during fasting.
• Insig2a mRNA expression decreased in refed mice.
• A functional PPAR-responsive element was identified in the Insig2a promoter, confirming PPARα's role in enhancing Insig2a gene expression.

Conclusions:

• PPARα acts as a trans-acting factor that enhances Insig2a gene expression.
• This PPARα-mediated upregulation of Insig2a suppresses SREBP-1c processing during fasting.
• The findings clarify a key regulatory pathway in hepatic fatty acid and cholesterol metabolism.