Acbd5

ACBD5 (acyl‑CoA binding domain containing protein 5) is a protein encoded by the ACBD5 gene located on chromosome 9q34.3 in humans. It contains an N‑terminal acyl‑CoA binding (ACB) domain that confers the ability to bind long‑chain fatty acids and acyl‑CoA thioesters, and a C‑terminal transmembrane segment that anchors the protein in the peroxisomal membrane. The protein is ubiquitously expressed, with higher levels in liver, skeletal muscle and adipose tissue, reflecting its role in systemic lipid metabolism.

ACBD5 acts as a tether between peroxisomes and the endoplasmic reticulum (ER) through direct interaction with the ER‐resident VAPB protein. This lipid‑transfer bridge facilitates the exchange of phospholipids and fatty acids between the two organelles and is essential for peroxisomal biogenesis and function. Knockdown of ACBD5 in cultured cells disrupts peroxisome morphology, impairs peroxisomal β‑oxidation, and leads to accumulation of very‑long‑chain fatty acids, underscoring its functional importance.

Genetic variants in ACBD5 have been implicated in a subset of peroxisomal biogenesis disorders, although the phenotype is less severe than in PEX gene mutations. Mouse models lacking Acbd5 exhibit altered lipid profiles, reduced fatty‑acid oxidation capacity, and mild neurobehavioral changes, supporting a conserved role in energy homeostasis. ACBD5 overexpression in hepatocytes has been shown to enhance fatty‑acid uptake and oxidation, suggesting potential therapeutic implications for metabolic diseases such as non‑alcoholic fatty liver disease.

The protein is regulated at the transcriptional level by PPARα and is subject to post‑translational modification by phosphorylation, which modulates its interaction with VAPB. Ongoing research aims to clarify ACBD5’s role in lipid signaling pathways and its potential as a target in metabolic disorders.