Competing tissue-specific functions for the Tribbles-1 plasma lipid associated locus

Area of Science:

• Biochemistry and Molecular Biology
• Genetics and Genomics
• Cardiovascular and Metabolic Research

Background:

• Genome-wide association studies (GWAS) have identified the pseudokinase Tribbles-1 (TRIB1) as a significant locus associated with multiple human cardiometabolic traits.
• These traits include alterations in plasma lipids and the development of atherosclerosis, highlighting TRIB1's critical role in metabolic health.

Purpose of the Study:

• To review recent advancements in understanding the functional roles of TRIB1 in cardiometabolic regulation.
• To identify outstanding questions and future research directions concerning TRIB1's involvement in metabolic diseases.

Main Methods:

• Investigation of TRIB1 function in a myeloid-specific Trib1 mouse model to assess its role in foam cell formation.
• Utilizing a 3D hepatic organoid model to recapitulate and study hepatic TRIB1 functions.
• Analysis of TRIB1's role in the mechanism of action of the lipid-lowering drug berberine.

Main Results:

• TRIB1 was shown to contribute to foam cell formation in a myeloid-specific mouse model, emphasizing tissue-specific functions.
• Hepatic TRIB1 functions observed in mouse models were successfully replicated in 3D hepatic organoid systems.
• Berberine, a known lipid-lowering drug, was found to act via a TRIB1-dependent pathway, revealing a novel regulator of TRIB1 expression.

Conclusions:

• TRIB1 is a key player in cardiometabolic regulation, with significant implications for lipid metabolism and atherosclerosis.
• Further research into tissue-specific TRIB1 functions, its regulation, and its role in therapeutic interventions is crucial.
• Translating findings from mouse models to human contexts and exploring TRIB1's involvement with existing therapeutics offers promising avenues for future studies.