Abstract
Hepatic stellate cells (HSC) are the major cellular drivers of liver fibrosis. Upon liver inflammation caused by a broad range of insults including non-alcoholic fatty liver, HSC transform from a quiescent into a proliferating, fibrotic phenotype. Although much is known about the pathophysiology of this process, exact cellular processes which occur in HSC and enable this transformation remain yet to be elucidated. In order to investigate this HSC transformation, we employed a simple, yet reliable model of HSC activation via an increase in growth medium serum concentration (serum activation). For that purpose, immortalized human LX-2 HSC were exposed to either 1% or 10% fetal bovine serum (FBS). Resulting quiescent (1% FBS) and activated (10% FBS) LX-2 cells were then subjected to in-depth mass spectrometry-based proteomics analysis as well as comprehensive phenotyping. Protein network analysis of activated LX-2 cells revealed an increase in the production of ribosomal proteins and proteins related to cell cycle control and migration, resulting in higher proliferation and faster migration phenotypes. Interestingly, we also observed a decrease in the expression of cholesterol and fatty acid biosynthesis proteins in accordance with a concomitant loss of cytosolic lipid droplets during activation. Overall, this work provides an update on HSC activation characteristics using contemporary proteomic and bioinformatic analyses and presents an accessible model for HSC activation. Data are available via ProteomeXchange with identifier PXD029121.
Highlights
Liver fibrosis is the replacement of parenchymal liver tissue by non-parenchymal scar tissue [1]
We treated Lieming Xu 2 (LX-2) cells with either 1% or 10% fetal bovine serum (FBS) for 24 h. Their activation status was confirmed by investigation of α-smooth muscle actin (α-SMA; Figure 1), a protein highly expressed in activated hepatic stellate cells (HSC) which enhances the contractility of cells [20] and has been prominently featured as a reliable marker for HSC activation [20,21,22]
We investigated whether the serum activation of LX-2 cells was reversible
Summary
Liver fibrosis is the replacement of parenchymal liver tissue by non-parenchymal scar tissue [1]. This process mostly occurs due to liver inflammation from alcohol abuse [2], viral infection [3], or a non-alcoholic fatty liver [4]. HSC transform from a quiescent (resting) phenotype towards a myofibroblast-like phenotype [1]. This transformation, termed “activation”, is a key event in liver fibrosis [10]. If we can improve our understanding of the cellular and molecular processes involved in HSC activation, we might identify targets to revert HSC to their quiescent phenotype, alleviating fibrosis in a damaged liver
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