Department of Internal Medicine, Keimyung University School of Medicine, Daegu 42601, Korea.
Institute for Medical Science, Keimyung University School of Medicine, Daegu 42601, Korea.
Cells. 2022 Aug 30;11(17):2704. doi: 10.3390/cells11172704.
Autophagy performs essential cell functions in the liver through an intracellular lysosomal degradation process. Several studies have reported that autophagy deficiency can lead to liver injury, including hepatic fibrosis; however, the mechanisms underlying the relationship between autophagy deficiency and liver pathology are unclear. In this study, we examined the expression levels of fibrosis-associated genes in hepatocyte-specific ATG7-deficient mice. The expression levels of the connective tissue growth factor (CTGF) and phosphorylated ERK (phospho-ERK) proteins were increased significantly in primary hepatocytes isolated from hepatocyte-specific ATG7-deficient mice compared to those isolated from control mice. In addition, the inhibition of autophagy in cultured mammalian hepatic AML12 and LX2 cells increased CTGF and phospho-ERK protein levels without altering CTGF mRNA expression. In addition, the autophagy deficiency-mediated enhancement of CTGF expression was attenuated when ERK was inhibited. Overall, these results suggest that the inhibition of autophagy in hepatocytes increases phospho-ERK expression, which in turn increases the expression of CTGF, a biomarker of fibrosis.
自噬通过细胞内溶酶体降解过程在肝脏中发挥重要的细胞功能。几项研究报告称，自噬缺陷可导致肝损伤，包括肝纤维化；然而，自噬缺陷与肝病理之间关系的机制尚不清楚。在这项研究中，我们检查了肝细胞特异性 ATG7 缺陷型小鼠中纤维化相关基因的表达水平。与从对照小鼠中分离的原代肝细胞相比，从肝细胞特异性 ATG7 缺陷型小鼠中分离的原代肝细胞中结缔组织生长因子 (CTGF) 和磷酸化 ERK (phospho-ERK) 蛋白的表达水平显著增加。此外，在培养的哺乳动物肝 AML12 和 LX2 细胞中抑制自噬会增加 CTGF 和磷酸化 ERK 蛋白水平，而不改变 CTGF mRNA 表达。此外，当 ERK 被抑制时，自噬缺陷介导的 CTGF 表达增强减弱。总的来说，这些结果表明，肝细胞中自噬的抑制会增加磷酸化 ERK 的表达，进而增加纤维化生物标志物 CTGF 的表达。
