ACLY as a modulator of liver cell functions and its role in Metabolic Dysfunction-Associated Steatohepatitis
Convertini, P. et al. (2023) ACLY as a modulator of liver cell functions and its role in Metabolic Dysfunction-Associated Steatohepatitis. J Transl Med. 21(1), 568. DOI: 10.1186/s12967-023-04431-w
The liver is a central hub for energy metabolism, integrating systemic metabolic signals from the brain and hormones to supply the body with its nutritional needs and metabolic outputs. However, metabolic dysfunctions have negative implications for liver function and can contribute to the development of liver failure and chronic liver damage. Two of the most common causes of liver failure and damage include Metabolic (Dysfunction)-Associated Fatty Liver Disease (MAFLD) and Metabolic (Dysfunction)-Associated Steatohepatitis (MASH), previously known as Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH), respectively. This new naming convention highlights the metabolic component of the pathophysiology affiliated with these diagnoses.
In this study, researchers evaluated the role of hepatic ATP citrate lyase (ACLY), an enzyme that plays a critical role in metabolic pathways and gene regulation, in TNFα-stimulated human hepatocytes (HH) and in peripheral blood mononuclear cells (PBMC)-derived macrophages from MASH patients. The inhibition of ACLY in TNFα-stimulated HH with either hydroxycitrate (HCA) or red wine powder (RWP) led to reverted lipid accumulation and oxidative damage in addition to a reduction in inflammatory cytokine secretion. These results suggest that ACLY’s effects are not only applicable to lipid metabolism but other aspects of liver function such as redox status. In MASH patients, elevated levels of ACLY and malic enzyme 1 (ME1), another key metabolic enzyme, were observed in PBMC-derived macrophages compared to healthy controls, suggesting that changes in ACLY levels also impact systemic processes. Furthermore, PBMC-derived macrophages from MASH patients treated with both HCA and RWP significantly reduced ACLY and ME1 mRNA expression as well as concentrations of proinflammatory cytokines IL-6 and IL-1β. Together, these results elucidate the diverse functions of ACLY in liver physiology and in the pathogenesis of MASH. This study also reveals ACLY as a potential diagnostic and therapeutic target for MASH.
Keywords: ATP citrate lyase (ACLY), hepatocytes, Metabolic Dysfunction-Associated Steatohepatitis (MASH), oxidative stress, NF-kB
