Role of Neutrophils in the Development of Steatotic Liver Disease.

This review explores the biological aspects of neutrophils, their contributions to the development of steatotic liver disease, and their potential as therapeutic targets for the disease. Although alcohol-associated and metabolic dysfunction-associated liver diseases originate from distinct etiological factors, the two diseases frequently share excessive lipid accumulation as a common contributor to their pathogenesis, thereby classifying them as types of steatotic liver disease. Dysregulated lipid deposition in the liver induces hepatic injury, triggering the activation of the innate immunity, partially through neutrophil recruitment. Traditionally recognized for their role in microbial clearance, neutrophils have recently garnered attention for their involvement in sterile inflammation, a pivotal component of steatotic liver disease pathogenesis. In conclusion, technological innovations, including single-cell RNA sequencing, have gradually disclosed the existence of various neutrophil subsets; however, how the distinct subsets of neutrophil population contribute differentially to the development of steatotic liver disease remains unclear.

Dimethyloxalylglycine Suppresses SREBP1c and Lipogenic Gene Expressions in Hepatocytes Independently of HIF1A.

Dimethyloxalylglycine (DMOG) is a representative inhibitor of the prolyl hydroxylase domain (PHD), which mediates the degradation of hypoxia-inducible factor-1-alpha (HIF1A). DMOG exerts its pharmacological effects via the canonical pathway that involves PHD inhibition; however, it remains unclear whether DMOG affects lipogenic gene expression in hepatocytes. We aimed to elucidate the effects of DMOG on sterol regulatory element-binding protein-1c (SREBP1c), a master regulator of fatty acid synthesis in hepatocytes. DMOG treatment inhibited SREBP1c mRNA and protein expression in HepG2 and AML12 hepatocytes and reduced the transcript levels of SREBP1c-regulated lipogenic genes. A luciferase reporter assay revealed that DMOG inhibited the transcriptional activity of SREBP1c. Moreover, DMOG suppressed SREBP1c expression in mice liver. Mechanistically, treatment with DMOG enhanced the expression of HIF1A and insulin-induced gene 2 (INSIG2), which inhibits the activation of SREBP1c. However, HIF1A or INSIG2 knockdown failed to reverse the inhibitory effect of DMOG on SREBP1c expression, suggesting a redundant role of HIF1A and INSIG2 in terms of repressing SREBP1c. DMOG did not function through the canonical pathway involving inhibition of SREBP1c by PHD, highlighting the presence of non-canonical pathways that mediate its anti-lipogenic effect.

Inflammation in Alcohol-Associated Hepatitis: Pathogenesis and Therapeutic Targets.

Alcohol-associated hepatitis (AH) is an acute-on-chronic liver injury that occurs in patients with chronic alcohol-associated liver disease (ALD). Patients with severe AH have high short-term mortality and lack effective pharmacologic therapies. Inflammation is believed to be one of the key factors promoting AH progression and has been actively investigated as therapeutic targets over the last several decades, but no effective inflammatory targets have been identified so far. In this review, we discuss how inflammatory cells and the inflammatory mediators produced by these cells contribute to the development and progression of AH, with focus on neutrophils and macrophages. The crosstalk between inflammatory cells and liver nonparenchymal cells in the pathogenesis of AH is elaborated. We also deliberate the application of recent cutting-edge technologies in characterizing liver inflammation in AH. Finally, the potential therapeutic targets of inflammatory mediators for AH are briefly summarized.