ERK1/2 regulates hepatocyte Trib1 in response to mitochondrial dysfunction

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• The TRIB1 gene locus (8q24.13) is associated with plasma triglycerides, apolipoprotein B, and coronary artery disease.
• Tribbles-like protein 1 (Trib1) regulates mitogen-activated protein kinase (MAPK) signaling, impacting cellular responses and hepatic lipogenesis.
• The mechanisms regulating hepatocyte Trib1, crucial for lipid metabolism and atherosclerosis, are not well understood.

Purpose of the Study:

• To investigate the regulatory mechanisms controlling Trib1 expression.
• To identify novel regulators of Trib1, particularly in the context of cellular stress.

Main Methods:

• Treatment of HepG2, HuH7 cells, and murine hepatocytes with mitochondrial stressors (e.g., oligomycin).
• Analysis of Trib1 mRNA and protein levels.
• Investigation of the role of reactive oxygen species, metabolic stress, and ERK1/2 signaling.

Main Results:

• Mitochondrial stressors, including low-dose oligomycin, potently and persistently increase Trib1 mRNA levels in HepG2 cells.
• Upregulation of Trib1 mRNA was observed in HuH7 cells and murine hepatocytes, though to a lesser extent.
• The Trib1 mRNA increase was largely independent of reactive oxygen species or metabolic stress and primarily transcriptionally controlled, involving ERK1/2.
• Attempts to correlate increased mRNA with protein levels were unsuccessful due to a lack of a recognizable Trib1 signal.

Conclusions:

• The mitochondria axis is identified as a novel regulator of Trib1 expression.
• MAPK signaling, specifically ERK1/2, plays a role in regulating Trib1 transcription.
• This study uncovers a feedback mechanism where MAPK signaling regulates Trib1, adding to its known role as a MAPK pathway activator.