Cell Autophagy in NASH and NASH-Related Hepatocellular Carcinoma - PubMed (original) (raw)

Review

Utibe-Abasi S Udoh et al. Int J Mol Sci. 2022.

Abstract

Autophagy, a cellular self-digestion process, involves the degradation of targeted cell components such as damaged organelles, unfolded proteins, and intracellular pathogens by lysosomes. It is a major quality control system of the cell and plays an important role in cell differentiation, survival, development, and homeostasis. Alterations in the cell autophagic machinery have been implicated in several disease conditions, including neurodegeneration, autoimmunity, cancer, infection, inflammatory diseases, and aging. In non-alcoholic fatty liver disease, including its inflammatory form, non-alcoholic steatohepatitis (NASH), a decrease in cell autophagic activity, has been implicated in the initial development and progression of steatosis to NASH and hepatocellular carcinoma (HCC). We present an overview of autophagy as it occurs in mammalian cells with an insight into the emerging understanding of the role of autophagy in NASH and NASH-related HCC.

Keywords: NASH; NASH-related HCC; cell autophagy.

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Conflict of interest statement

The authors have no conflict of interest to declare with respect to authorship and publication of this article.

Figures

Figure 1

Figure 1

Autophagic pathways in mammalian cells. There are three major autophagic processes identified in most mammalian cells. (A) Macro-autophagy: in MA, cytosolic substrates determined to be transported are first packaged into autophagosomes, which are double-membrane vesicles formed through conjugation of autophagy-related proteins (i.e., Atg5, Atg12, Atg16) and autophagy-related protein LC3 with lipid PE. The formation of these autophagosomes is initiated by the phosphorylation of lipids in the membrane of organelles such as the endoplasmic reticulum, mitochondria, and Golgi apparatus, triggered by a kinase complex regulated by Beclin-1. Autophagosomes are targeted to lysosomes, and, after fusion of both vesicles, the cargo is delivered to the lysosomes for complete degradation. (B) Micro-autophagy: the in-bulk mA pathway allows cytosolic proteins and organelles to be degraded in bulk through invaginations at the lysosomal membrane. Through endosomal mA, cytosolic proteins can be selectively identified by Hsc70 to be transported to late endosomes using the KFERQ-like motif on the target proteins, leading to their internalization and degradation in the lysosomes. (C) Chaperone mediated autophagy: proteins in the cytosol with a KFERQ-like motif in their sequence can be identified by a molecular chaperone, Hsc70, and brought to the lysosomal membrane for translocation across the LAMP-2A multimeric complex. Lysosomal Hsc70 assist the translocation of the substrate protein, which is then degraded once inside the lysosomes (Adapted and modified from Scrivo et al. 2018) [20].

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This review was funded by a Grant to Dr. J Sanabria from the Edwards Comprehensive Cancer Center.

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