Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

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: hepatic stellate cell; liver fibrosis; metabolism; trans-differentiation.

Figure 1

The space of Disse. Quiescent stellate cells located in the space of Disse undergo activation in response to a number of different stimuli, such as growth factors, cytokines or debris, and molecules derived from apoptotic hepatocytes. See text for details.

Figure 2

Scheme of retinol metabolism. Retinol (ROL) is imported from hepatocytes into HSCs being bound to retinol-binding protein (RBP). Upon its release, it is esterified by lecithin:retinol acyltransferase (LRAT) or diacylglycerol O-acyltransferase 1 (DGAT) and stored in lipid droplets (LD). Mobilization of retinol from lipid droplets is mediated by several enzymes including patatin-like phospholipase domain-containing protein 3 (PNPLA3), lipoprotein lipase (LPL), pancreatic-related protein 2 (mPlrp2), and procolipase (mClps). Retinol can be oxidized to retinal by retinol dehydrogenases (RDH), and the aldehyde can be oxidized to form all-trans retinoic acid (ATRA) by aldehyde dehydrogenase 1A (ALDH1A) isoforms. ATRA can be transferred to the nucleus when bound to Cellular retinoic acid-binding protein (CRABP), where it induces nuclear RA receptors (RARs) or retinoid X receptors (RXRs) to induce transcription of genes carrying retinoic acid response elements (RARE) in their promoters. Alternatively, ATRA can be metabolized by cytochrome P450 isoforms, and the resulting products are exported from cells. Genes that are up- or down-regulated during activation of HSCs are shown in red and green, respectively.

Figure 3

Features of quiescent and activated hepatic stellate cells. See text for details.

Figure 4

Central carbon metabolism. Glucose is taken up by glucose transporters (Glut) and then phosphorylated by hexokinase (HK) to produce glucose-6-phosphate (G6P). G6P can be channeled by glucose-6-phosphate dehydrogenase (G6PDH) into the pentose phosphate pathway for nucleotide production. Alternatively, G6P can be converted to fructose-6-phosphate (F6P), fructose-1,6-bisphosphate (FBP), glyceraldehyde 3-phosphate (GAP), 1,3-bisphosphoglycerate (1,3-BPG), and 3-phosphoglycerate (3PG) under catalysis of phosphoglucoisomerase (PGI), phosphofructokinase (PFK), aldolase (Aldo), glyceraldehyde dehydrogenase (GAPDH), and phosphoglycerokinase (PGK), respectively. 3PG is a precursor for de novo serine synthesis via 3-phosphopyruvate (3PPyr) and 3-phosphoserine (3PSer). Serine is converted to glycine to feed methionine and folate metabolism (one carbon metabolism). Serine/glycine biosynthesis is catalyzed by phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT), phosphoserine phosphatase (PSPH), and serine hydroxymethyltransferase 2 (SHMT2). Alternatively, 3PG is converted into pyruvate (PYR) via 2-phosphoglycerate (2PG) and phosphoenolpyruvate (PEP) with phosphoglyceromutase (PGM), enolase (Enol), and pyruvate kinase (PK) catalysis. Pyruvate is imported into mitochondria and either channeled to the tricarbonic acid (TCA) cycle via pyruvate dehydrogenase (PDH)-catalyzed formation of acetyl coenzyme A (AcCoA) or via pyruvate carboxylase (PC). Pyruvate can be also transformed into lactate through lactate dehydrogenase (LDH) and then be exported from a cell via monocarboxylate transporters (MCT). Glutamine can also serve as substrate for the TCA cycle. Glutaminolysis refers to the import of glutamine (Gln) and its conversion into glutamate (Glu) and α-ketoglutarate (αKG) through glutaminase (GLS) and glutamate dehydrogenase (GLUD). Within the TCA cycle, αKG is converted into succinyl-CoA (SucCoA), succinate (SUC), and fumarate (FUM) via α-ketoglutarate dehydrogenase (αKGDH), succinyl-CoA synthetase (SCS), and succinate dehydrogenase (SDH), respectively. Fumarate is converted into citrate (CIT) via malate (MAL) and oxaloacetate (OAA), and these reactions are accomplished by fumarase (FH), malate dehydrogenase (MDH), and citrate synthase (CS). Finally, citrate converted by aconitase (Aco) to isocytrate (ISO), and the latter is isomerized and then transformed into αKG with isocitrate dehydrogenase (IDH). Hypoxia-inducible factor 1α (HIF1α) upregulates expression of Glut1, HK2, PK, and PDK3, thus enhancing glycolysis but preventing shuttling of pyruvate into the TCA cycle. Cytochrome P450 2E1 (CYP2E1) activates a cascade (see the text for details) which leads to phosphorylation of alpha serine/threonine-protein kinase (AKT) and concomitant increase in Glut4 expression, thus also contributing to stimulated glycolysis. The Hedgehog (Hh)-YAP pathway upregulates expression of glutaminase 1 (GLS1). A TCA cycle intermediate succinate (also shown in red) may contribute to fibrogenesis by activating G protein-coupled receptor 91 (GPR91), also known as a succinate receptor.