Modulation of Fatty Acid Metabolism via Lactate-HCA1 Signaling: Potential Therapeutic Implications

The lactate/HCA1 signaling pathway has emerged as a promising target for the clinical management of metabolic diseases, given its regulatory effects on triglyceride turnover and mobilization. However, the differential roles of this pathway in adipose tissue, skeletal muscle, and the liver raise important questions about whether its activation or inhibition would yield the most favorable outcomes. In adipose tissue, HCA1 activation suppresses lipolysis, while in skeletal muscle, recent evidence suggests that lactate may bypass HCA1 to directly enhance mitochondrial fatty acid oxidation. In the liver, HCA1 activation has been implicated in promoting lipid oxidation, offering potential therapeutic implications. This perspective also explores the potential of the lactate/HCA1 pathway to mediate systemic adaptations induced by exercise training, including enhanced mitochondrial capacity and metabolic flexibility. These insights underscore the pathway's relevance for both metabolic health and exercise physiology. However, the current understanding of the lactate/HCA1 pathway remains incomplete, with critical gaps in knowledge regarding its role in underrepresented populations and the molecular mechanisms underlying its tissue-specific effects. Addressing these limitations will be essential for refining the therapeutic and clinical applications of this pathway.