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Abstract <p>Autophagy is a dynamic process of delivery of non-functional cytoplasmic components into lysosomes for subsequent degradation, serving to renew cellular contents and utilize protein aggregates and organelles. This process is necessary to maintain cell metabolism under conditions of energy and nutrient deficiency. The pathogenesis of aging-associated diseases is associated with disturbances in the autophagy process. In the liver of senescent-accelerated OXYS rats and Wistar rats (control) at the age of 4 and 16 months, the transcriptional activity of key genes of the autophagy process was studied during its induction by fasting (12, 24 and 48 h) and inhibition by chloroquine. At the age of 4 months, modulation of autophagy in the liver of rats revealed changes in the mRNA level of the <i>Atg7</i>, <i>Gabarapl1</i>, <i>Nbr1</i> and p62/<i>Sqstm1</i> genes. At the age of 16 months, in response to food deprivation, the mRNA level of the <i>Atg7</i>, <i>Map1lc3b</i>, <i>Gabarapl1</i> and <i>Nbr1</i> genes increased, and the dynamics of changes in their expression depended on the genotype of the animals. Interstrain differences were revealed in the mRNA levels of <i>Atg7</i> at 4 months and <i>Gabarapl1</i> at 16 months during administration of chloroquine, which neutralized the effects of fasting. Our study is the first to demonstrate the effect of chloroquine on the transcriptional activity of autophagy-associated genes in rat liver. The effects of chloroquine (a late-stage autophagy blocker) on autophagy-related gene expression were age- and genotype-dependent, providing direct evidence of altered autophagic flux in the liver with aging. The observed strain-specific differences in autophagy-related gene expression in response to modulation suggest variations in the baseline state and reactivity of hepatic autophagy between OXYS and Wistar rats. These differences may contribute to the accelerated aging phenotype in OXYS rats. Given the established connection between metabolic homeostasis and aging pathologies, we hypothesize that targeting autophagic flux could represent a strategy for regulating hepatic metabolism in age-related decline.</p>

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Transcriptional Responses of Autophagy-Related Genes in the Rat Liver to Fasting and Chloroquine Treatment

  • 期刊论文

  • 发表日期：

    2025年9月1日

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  • O. S. Kozhevnikova,
  • D. V. Telegina,
  • N. G. Kolosova

摘要

Abstract

Autophagy is a dynamic process of delivery of non-functional cytoplasmic components into lysosomes for subsequent degradation, serving to renew cellular contents and utilize protein aggregates and organelles. This process is necessary to maintain cell metabolism under conditions of energy and nutrient deficiency. The pathogenesis of aging-associated diseases is associated with disturbances in the autophagy process. In the liver of senescent-accelerated OXYS rats and Wistar rats (control) at the age of 4 and 16 months, the transcriptional activity of key genes of the autophagy process was studied during its induction by fasting (12, 24 and 48 h) and inhibition by chloroquine. At the age of 4 months, modulation of autophagy in the liver of rats revealed changes in the mRNA level of the Atg7, Gabarapl1, Nbr1 and p62/Sqstm1 genes. At the age of 16 months, in response to food deprivation, the mRNA level of the Atg7, Map1lc3b, Gabarapl1 and Nbr1 genes increased, and the dynamics of changes in their expression depended on the genotype of the animals. Interstrain differences were revealed in the mRNA levels of Atg7 at 4 months and Gabarapl1 at 16 months during administration of chloroquine, which neutralized the effects of fasting. Our study is the first to demonstrate the effect of chloroquine on the transcriptional activity of autophagy-associated genes in rat liver. The effects of chloroquine (a late-stage autophagy blocker) on autophagy-related gene expression were age- and genotype-dependent, providing direct evidence of altered autophagic flux in the liver with aging. The observed strain-specific differences in autophagy-related gene expression in response to modulation suggest variations in the baseline state and reactivity of hepatic autophagy between OXYS and Wistar rats. These differences may contribute to the accelerated aging phenotype in OXYS rats. Given the established connection between metabolic homeostasis and aging pathologies, we hypothesize that targeting autophagic flux could represent a strategy for regulating hepatic metabolism in age-related decline.