The absence of the alpha-7 nicotinic acetylcholine receptor impairs liver regeneration due to altered autophagic response after resection

INTRODUCTION AND OBJECTIVES: The α7 nicotinic acetylcholine receptor (α7nAChR) plays a central role in modulating inflammation and cellular homeostasis. However, its role in liver regeneration remains poorly understood. MATERIAL AND METHODS: The role of α7nAChR in liver regeneration was investigated in Chrna7⁻/⁻ mice and wild-type controls subjected to partial hepatectomy (PHx), focusing on autophagy markers. RESULTS: During the priming phase, Chrna7⁻/⁻ mice presented increased levels of adiponectin and IL6 transcripts compared to WT. Female Chrna7⁻/⁻ mice exhibited impaired STAT3 phosphorylation and p62 and LC3-II accumulation, increased protein ubiquitination, and reduced Atg5 gene expression compared to WT. These early defects worsened during the proliferative phase, with increased lipid accumulation, decreased KI67 and PCNA, and sustained modulation of autophagy markers, leading to compromised hepatocyte proliferation and higher mortality. In males, the priming phase was characterized by reduced JAK2 expression but activation of compensatory pathways, such as increased pAMPK and elevated protein ubiquitination in Chrna7⁻/⁻ mice, alongside hints of autophagy changes shown by p62 and LC3-II accumulation, compared to WT. The proliferative phase was marked by increased lipid accumulation and reduced KI67 and PCNA. Alongside a paradoxical autophagic state, characterized by downregulated autophagosome formation genes (Atg5 and Beclin1) with elevated LC3-II and decreased p62 (markers of autophagic flux), suggests a differential modulation of the autophagic machinery. CONCLUSIONS: Overall, α7nAChR deficiency led to impaired liver regeneration through distinct sex-specific changes in autophagy markers, resulting in increased mortality. These findings underscore α7nAChR as critical for autophagy homeostasis during liver regeneration and its potential as a therapeutic target.