Cytoskeleton alterations in non-alcoholic fatty liver disease

Abstract

Background: Due to its extremely high prevalence and severity, non-alcoholic fatty liver disease (NALFD) is a serious health and economic concern worldwide.Developing effective methods of diagnosis and therapy demands a deep understanding of its molecular basis. One of the strategies in such an endeavor is the analysis of alterations in the morphology of liver cells. Such alterations, widely reported in NAFLD patients and disease models, are related to the cytoskeleton. Therefore, the fate of the cytoskeleton components is useful to uncover the molecular basis of NAFLD, to further design innovative approaches for its diagnosis and therapy.Main findings: Several cytoskeleton proteins are up-regulated in liver cells of NAFLD patients. Under pathological conditions, keratin 18 is released from hepatocytes and its detection in the blood emerges as a non-invasive diagnosis tool. α-Smooth muscle actin is up-regulated in hepatic stellate cells and its downregulation has been widely tested as a potential NALFD therapeutic approach.Other cytoskeleton proteins, such as vimentin, are also up-regulated.Conclusions: NAFLD progression involves alterations in expression levels of proteins that build the liver cytoskeleton or associate with it. These findings provide a timely opportunity of developing novel approaches for NAFLD diagnosis and therapy.

Plasma Cytokeratin-18 Fragment Level Reflects the Metabolic Phenotype in Obesity

“…The progression of MAFLD involves hepatocyte swelling and alterations in proteins that build the cytoskeleton. An analysis of cytoskeleton proteins may provide some information on the molecular basis of MAFLD pathogenesis and improve the NAFLD diagnosis and staging, especially in terms of the transition from benign simple steatosis to irreversible steatohepatitis [ 6 ].…”

Adipose tissue insulin resistance exacerbates liver inflammation and fibrosis in a diet-induced NASH model

“…The KEGG pathway analysis showed that these 354 genes were enriched in pathways including extracellular matrix (ECM)–receptor interaction, regulation of actin cytoskeleton, and focal adhesion (Figure 3 B), all of which are also implicated in NASH pathogenesis. 26 Collectively, these results, thus, suggested that various genes in the identified pathways may additively or independently contribute to NASH pathogenesis, including the fibrosis and inflammation induced by the GAN diet or adipocyte-specific PDK1 deficiency.…”

“…Recent studies have also implicated changes in the cytoskeleton in the pathophysiology of NAFLD-NASH. 26 Cytoskeletal organization responds to changes in the extracellular environment, including those in the ECM and cytokines-chemokines. 37 , 38 Adipocyte-specific PDK1 deficiency and the GAN diet may, therefore, mutually promote inflammation and fibrosis in the liver through mechanisms related to interactions between the extracellular environment and the cytoskeleton in hepatocytes and nonparenchymal cells.…”