ACSL5

ACSL5 Full Name

acyl-CoA synthetase long-chain family member 5

ACSL5 Introduction

Acyl-CoA synthetase long-chain family member 5 (ACSL5) is a critical isozyme of the ACSL family, primarily localized to the endoplasmic reticulum and the outer mitochondrial membrane. Its fundamental biochemical function is to catalyze the initial, rate-limiting thioesterification of long-chain fatty acids (typically containing 16 to 20 carbon atoms) into highly active fatty acyl-CoA esters. This ATP-dependent activation is a strict biological prerequisite, as free fatty acids remain metabolically inert until they are activated to enter either anabolic pathways, such as complex lipid synthesis, or catabolic pathways, like mitochondrial beta-oxidation. Physiologically, ACSL5 is distinctively abundant in the small intestinal mucosa, where it accounts for a significant majority of total cellular ACSL activity. Within enterocytes, ACSL5 specifically directs activated fatty acids toward triacylglycerol synthesis and the subsequent formation of cytosolic lipid droplets. Through this targeted channeling, the enzyme plays an indispensable role in dietary lipid absorption, intestinal metabolism, and the maintenance of systemic energy homeostasis.

Figure 1. Role of ACSL5 in fatty acid metabolism in rat hepatocytes and effects on circulating lipids. (Source: Luo Q, et al. 2023)

Clinically, the dysregulation of ACSL5 is increasingly recognized as a key pathological driver in metabolic disorders and malignancies. In hepatic metabolism, decreased ACSL5 expression is closely associated with the onset and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Recent evidence demonstrates that stabilizing hepatic ACSL5 actively promotes fatty acid beta-oxidation, thereby preventing pathological fat accumulation, cellular inflammation, and severe liver fibrosis. In the field of oncology, ACSL5 exhibits a complex, highly context-dependent duality. While it functions as a beneficial tumor suppressor in certain gastrointestinal cancers by promoting cellular apoptosis and mucosal differentiation, it acts as a critical oncogenic driver in systemic malignancies like acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC). In these aggressive cancers, ACSL5 facilitates profound lipid metabolic reprogramming, fueling rapid tumor proliferation and survival through the modulation of critical signaling networks, such as the Wnt/β-catenin pathway via targeted protein palmitoylation. Consequently, ACSL5 has emerged as a highly significant prognostic biomarker and a promising therapeutic target for treating both severe metabolic syndromes and combating chemoresistant cancers.

Alternate Names for ACSL5

ACSL5; acyl-CoA synthetase long-chain family member 5; FACL5, fatty acid Coenzyme A ligase, long chain 5; long-chain-fatty-acid--CoA ligase 5; ACS2; ACS5; FACL5 for fatty acid coenzyme A ligase 5; fatty acid Coenzyme A ligase; long chain 5; long chain acyl CoA synthetase 5

• 1. Luo Q, et al. Role of ACSL5 in fatty acid metabolism. Heliyon. 2023 Jan 31;9(2):e13316.
  2. Griffin JD, et al. Intestinal Acyl-CoA synthetase 5 (ACSL5) deficiency potentiates postprandial GLP-1 & PYY secretion, reduces food intake, and protects against diet-induced obesity. Mol Metab. 2024 May;83:101918.