TRIM5

Summary

TRIM5 (Tripartite motif-containing protein 5) is a gene encoding an E3 ubiquitin-protein ligase that plays a well-established role in innate immunity and antiviral host defense. Recent large-scale genome-wide association studies (GWAS) have identified genetic variants at the TRIM5 locus (such as the lead missense variant rs11601507, p.Val112Ile) that are strongly associated with circulating levels of 42 lipoprotein and lipid traits, as well as coronary artery disease (CAD) risk.

Role in Lipid Metabolism

The metabolic effects of the lead TRIM5 variant mirror those of the well-known HMGCR variant rs12916, showing a concordant signature with statin therapy. While the exact molecular mechanism remains to be fully elucidated, studies in mouse models of nonalcoholic fatty liver disease suggest that TRIM5 may mediate the degradation of DEAD-box protein 5, affecting mTORC1 signaling and the LDL receptor pathway, thereby impacting lipid accumulation and inflammation.

Therapeutic Potential

Because its metabolic profile aligns closely with genes that regulate LDL cholesterol intake by hepatocytes (like LDLR), TRIM5 has been proposed as a potential therapeutic target. Inhibiting TRIM5 could offer an alternative pathway to lower pro-atherogenic apoB-containing lipoproteins, which is of interest for individuals who are statin-intolerant or require further risk reduction.

Citations

• Karjalainen, M. K., Karthikeyan, S., Oliver-Williams, C., et al. (2024). Genome-wide characterization of circulating metabolic biomarkers. Nature, 628, 130–138. Source paper: s41586-024-07148-y.pdf