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Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

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Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis cells Review Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis Olga Khomich 1,2, Alexander V. Ivanov 2,* and Birke Bartosch 1,* 1 INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, CEDEX 03, 69424 Lyon, France; [email protected] 2 Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia * Correspondence: [email protected] (A.V.I.); [email protected] (B.B.); Tel.: +74-991-356-065 (A.V.I.); +33-472-681-975 (B.B.) Received: 28 October 2019; Accepted: 18 December 2019; Published: 20 December 2019 Abstract: Liver fibrosis is a regenerative process that occurs after injury. It is characterized by the deposition of connective tissue by specialized fibroblasts and concomitant proliferative responses. Chronic damage that stimulates fibrogenic processes in the long-term may result in the deposition of excess matrix tissue and impairment of liver functions. End-stage fibrosis is referred to as cirrhosis and predisposes strongly to the loss of liver functions (decompensation) and hepatocellular carcinoma. Liver fibrosis is a pathology common to a number of different chronic liver diseases, including alcoholic liver disease, non-alcoholic fatty liver disease, and viral hepatitis. The predominant cell type responsible for fibrogenesis is hepatic stellate cells (HSCs). In response to inflammatory stimuli or hepatocyte death, HSCs undergo trans-differentiation to myofibroblast-like cells. Recent evidence shows that metabolic alterations in HSCs are important for the trans-differentiation process and thus offer new possibilities for therapeutic interventions. The aim of this review is to summarize current knowledge of the metabolic changes that occur during HSC activation with a particular focus on the retinol and lipid metabolism, the central carbon metabolism, and associated redox or stress-related signaling pathways. Keywords: liver fibrosis; hepatic stellate cell; trans-differentiation; metabolism 1. Introduction to Liver Fibrosis Decompensation and hepatocellular carcinoma (HCC) due to liver cirrhosis are causing two million deaths every year, and account for more than 3.5% of all deaths worldwide [1]. HCC is the most common liver cancer and the second leading cause of all deaths related to cancer [2]. While the number of patients with liver disease has been steadily increasing over the last few years, treatment options for early, as well as late-stage liver fibrosis, remain limited. The most prevalent forms of fibrotic liver disease are alcoholic liver disease (ALD), non-alcoholic fatty liver disease, which frequently develops into non-alcoholic steatohepatitis (NASH) [3], and viral hepatitis. In all these cases, it is the chronic nature of the liver injury that drives fibrosis development. Fibrosis is a regenerative process that alters the homeostasis of the extracellular matrix (ECM) and leads on the long-term to excessive accumulation of connective tissue in the liver. Fibrosis is accompanied by immune infiltrations and altered angiogenesis. Together, these processes alter the architecture of the liver, reduce liver elasticity, and ultimately deteriorate organ structure and function [4]. Late-stage fibrosis, also termed cirrhosis, is characterized by the formation of nodules, where healthy liver tissue is ‘encapsulated’ by connective tissue. This results in liver stiffness and perturbation of blood flow with portal hypertension, and an increased risk of overall mortality and mortality due to liver decompensation or HCC. Cells 2020, 9, 24; doi:10.3390/cells9010024 www.mdpi.com/journal/cells Cells 2019, 8, x 2 of 22 with portal hypertension, and an increased risk of overall mortality and mortality due to liver decompensation or HCC. Most of the progress that has been made in the identification of the molecular mechanisms underlying fibrosis is based on the use of in vitro model systems using tissue culture‐adapted HSC Cellslines,2020 primary, 9, 24 HSC preparations, and a number of in vivo models such as animals being fed 2high of 22‐ fat/cholesterol or choline‐deficient diets, animals that undergo bile duct ligation, treatment with ethanol,Most CCl of4 the or other progress chemical that hasagents, been or made transgenic in the animals identification [5]. of the molecular mechanisms underlying fibrosis is based on the use of in vitro model systems using tissue culture-adapted 2. Hepatic Stellate Cells HSC lines, primary HSC preparations, and a number of in vivo models such as animals being fed high-fatThe/cholesterol cell type orthat choline-deficient is predominantly diets, responsible animals that for undergo fibrotic bileprocesses duct ligation, is hepatic treatment stellate with cells ethanol,(HSCs), CCla mesenchymal4 or other chemical cell population agents, or that transgenic constitutes animals 5%–10% [5]. of the total number of cells in the liver (Figure 1). HSCs are located in the perisinusoidal space (space of Disse) and are surrounded by 2.hepatocytes Hepatic Stellate and sinusoidal Cells endothelial cells [6,7]. Their main functions are the secretion of laminin, proteoglycans,The cell type and that type is predominantly IV collagen to responsible form basement for fibrotic membrane processes‐like is structures. hepatic stellate Quiescent cells (HSCs), HSCs astart mesenchymal to proliferate cell populationand undergo that trans constitutes‐differentiation 5–10% of into the totalcontractile number myofibroblasts of cells in the liver in response (Figure1 ).to HSCsparacrine are located stimulation in the perisinusoidalby neighboring space cell (spacetypes, of including Disse) and Kupffer are surrounded cells, hepatocytes, by hepatocytes platelets, and sinusoidalleukocytes, endothelial and sinusoidal cells endothelial [6,7]. Their cells. main Kupffer functions cells are can the stimulate secretion activation of laminin, and proteoglycans, proliferation andof HSCs type IVthrough collagen the to actions form basement of cytokines, membrane-like and in particular structures. transforming Quiescent growth HSCs startfactor to β proliferate1 (TGFβ1), andinterleukin undergo 1 trans-di (IL‐1), tumorfferentiation necrosis into factor contractile (TNF), myofibroblasts reactive oxygen in species response (ROS) to paracrine and lipid stimulation peroxides by[6,8]. neighboring Hepatocytes cell are types, an important including source Kupffer of cells, inflammatory hepatocytes, lipid platelets, peroxides leukocytes, in liver diseases. and sinusoidal Platelets endothelialrelease pro cells.‐fibrogenic Kupff ergrowth cells can factors stimulate such activationas platelet and‐derived proliferation growth of factor HSCs (PDGF), through TGF the actionsβ1, and ofepidermal cytokines, growth and in particularfactor (EGF). transforming Neutrophils growth are factoran importantβ1 (TGF βsource1), interleukin of ROS 1 as (IL-1), well tumor [6,8]. necrosisLymphocytes factor (TNF),represent reactive a further oxygen potential species source (ROS) of and pro lipid‐fibrogenic peroxides cytokines. [6,8]. Hepatocytes Finally, HSCs are anare importantresponsive source to locally of inflammatory produced or lipidsystemic peroxides levels inof livervaso‐ diseases.constricting Platelets peptides release and pro-fibrogenicfactors such as growthendothelin factors‐1 and such angiotensin as platelet-derived‐II. Endothelin growth‐1 factor is produced (PDGF), TGFprimarilyβ1, and by epidermal the liver growthendothelium. factor (EGF).Angiotensin Neutrophils‐II is secreted are an important by the liver source and of matured ROS as wellinto [6a, 8functional]. Lymphocytes peptide represent by a number a further of potentialproteolytic source cleavages of pro-fibrogenic and nitric oxide cytokines. to regulate Finally, the diameter HSCs are of responsive the sinusoidal to locally lumen produced and thus the or systemiclocal microcirculation. levels of vaso-constricting peptides and factors such as endothelin-1 and angiotensin-II. Endothelin-1Upon stimulation, is produced one primarily major activity by the liver of myofibroblasts endothelium. Angiotensin-IIis to produce collagen is secreted fibers. by the Besides liver andHSCs, matured liver progenitor into a functional cells and peptide portal by fibroblasts a number ofcan proteolytic also convert cleavages into myofibroblasts and nitric oxide in response to regulate to thepro diameter‐fibrogenic of thestimuli sinusoidal and contribute lumen and to collagen thus the secretion. local microcirculation. Figure 1. The space of Disse. Quiescent stellate cells located in the space of Disse undergo activation in Figure 1. The space of Disse. Quiescent stellate cells located in the space of Disse undergo activation response to a number of different stimuli, such as growth factors, cytokines or debris, and molecules in response to a number of different stimuli, such as growth factors, cytokines or debris, and derived from apoptotic hepatocytes. See text for details. molecules derived from apoptotic hepatocytes. See text for details. Upon stimulation, one major activity of myofibroblasts is to produce collagen fibers. Besides HSCs, liver progenitor cells and portal fibroblasts can also convert into myofibroblasts in response to pro-fibrogenic stimuli and contribute to collagen secretion. Quiescent HSCs store retinoids (vitamin A) in lipid droplets in the cytoplasm [8]. Retinoid derivatives play an important role in tissue homeostasis and are implicated in proliferation,
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