Polyunsaturated fatty acids suppress hepatic sterol regulatory element-binding protein-1 expression by accelerating...

Area of Science:

• Biochemistry
• Molecular Biology
• Nutritional Science

Background:

• Sterol regulatory element binding protein-1 (SREBP-1) regulates lipogenic gene transcription in the liver.
• Polyunsaturated fatty acids (PUFA) inhibit hepatic lipogenesis, but the underlying mechanisms are not fully understood.
• Previous studies indicated PUFA block insulin and glucose induction of SREBP-1 expression via post-transcriptional mechanisms.

Purpose of the Study:

• To investigate the effect of PUFA on SREBP-1 mRNA stability.
• To determine if PUFA influence the decay rates of SREBP-1a and SREBP-1c isoforms.
• To explore the role of translation in PUFA-mediated SREBP-1 mRNA decay.

Main Methods:

• Treatment of rat hepatocytes with specific PUFA (20:4(n-6) and 20:5(n-3)).
• Measurement of SREBP-1 mRNA half-life using ribonuclease protection assays.
• Assessment of SREBP-1 mRNA decay in the presence of the translational inhibitor cycloheximide.

Main Results:

• PUFA significantly enhance the decay rate of total SREBP-1 mRNA in hepatocytes, reducing its half-life by approximately 50%.
• SREBP-1c mRNA decay was more sensitive to PUFA than SREBP-1a mRNA, with half-lives decreasing from 10.0 to 4.6 h and 11.6 to 7.6 h, respectively.
• The PUFA-induced decay of SREBP-1 mRNA was inhibited by cycloheximide, suggesting a requirement for translation.

Conclusions:

• PUFA accelerate the degradation of SREBP-1 mRNA in liver cells through a post-transcriptional mechanism.
• The decay process appears to be dependent on or influenced by the translation of SREBP-1 mRNA.
• The 3'-untranslated region of SREBP-1 mRNA contains an AU-rich element, a known destabilizing feature, which may mediate PUFA effects.