Cell metabolism-based therapy for liver fibrosis, repair, and hepatocellular carcinoma

Abstract

Progression of chronic liver injury to fibrosis, abnormal liver regeneration, and HCC is driven by a dysregulated dialog between epithelial cells and their microenvironment, in particular immune, fibroblasts, and endothelial cells. There is currently no antifibrogenic therapy, and drug treatment of HCC is limited to tyrosine kinase inhibitors and immunotherapy targeting the tumor microenvironment. Metabolic reprogramming of epithelial and nonparenchymal cells is critical at each stage of disease progression, suggesting that targeting specific metabolic pathways could constitute an interesting therapeutic approach. In this review, we discuss how modulating intrinsic metabolism of key effector liver cells might disrupt the pathogenic sequence from chronic liver injury to fibrosis/cirrhosis, regeneration, and HCC.

FIGURE 1

Fibrogenesis, regeneration and cancer: a delicate balance. The same events that promote liver regeneration, particularly the activation of HSC, the induction of endothelial cell dysfunction and the switch of macrophages toward an inflammatory phenotype, drive liver fibrogenesis. During the first steps of fibrogenesis, hepatocytes maintain their proliferative capacity. When disease progress to cirrhosis, hepatocytes become senescent, show impaired proliferative capacity, and a ductular reaction made of cells with progenitor features develops around the portal tract. In this context of cirrhosis, an uncontrolled cell proliferation stimulus may lead to transformation of preneoplastic lesions to HCC. TAM and activated HSC, the precursor of CAF infiltrate HCC microenvironment stimulating tumor progression and invasiveness. A distinct HSC subpopulation with tumor-suppressive functions has also been recently identified. Abbreviations: CAF, cancer associated fibroblasts; TAM, tumor associated macrophages.

FIGURE 2

Main intrinsic metabolic pathways. Glucose enters the cell through glucose transporters and is converted into pyruvate through glycolysis. In parallel to glycolysis, the pentose phosphate pathway generates ribose 5 phosphate for the synthesis of nucleotides and amino acids. Pyruvate is either converted into lactate or is oxidized in acetyl coA, fueling the TCA cycle inside the mitochondria and giving rise to NADH and FADH2 that can also be produced by fatty acid oxidation. Fatty acid synthesis produces fatty acids from acetyl coA derived either from glycolysis or from citrate. The TCA cycle can also be fueled by amino acids through glutaminolysis. Abbreviations: ACC, acetyl-coenzyme A carboxylase; ACLY, ATP citrate lyase; CPT, carnitine palmitoyl transferase; GLUT, glucose transporter protein type; MUFA, monounsaturated fatty acid; PFK, phosphofructokinase; PKM2, pyruvate kinase isoform M2; SCD1, stearoyl-coA desaturase; TCA, tricarboxylic acid.

FIGURE 3

Role of intracellular metabolic pathways in liver fibrogenesis depending on the targeted cell type. The impact of the main intrinsic metabolic pathways (glycolysis, glutaminolysis, lipogenesis, autophagy, nuclear receptors and YAP/TAZ) on HSC activation, macrophage inflammatory phenotype, endothelial dysfunction, and hepatocyte injury and their consequences on liver fibrogenesis are depicted. Abbreviation: YAP/TAZ, yes-associated protein and the transcriptional coactivator with PDZ-binding motif.

FIGURE 4

Involvement of intrinsic metabolic pathways in liver regeneration. The consequence of the activation of various metabolic pathways (glycolysis, glutaminolysis, lipogenesis, autophagy, nuclear receptors, and YAP/TAZ) on hepatocyte proliferation either directly or indirectly through the secretion of cytokines, growth factors, or metalloproteinase by nonparenchymal liver cells is shown. Abbreviations: FXR, farnesoid X receptors; HK, hexokinase; MUFA, monounsaturated fatty acids; PPAR, peroxisome proliferator-activated receptors; YAP/TAZ, yes-associated protein and the transcriptional coactivator with PDZ-binding motif.

FIGURE 5

Targeting glycolysis for HCC therapy? Hexokinases (HK1 in HSC and HK2 in tumor cells) and PKM2 facilitate HCC progression through increased glycolysis in tumor cells and by promoting the dialog between tumor and microenvironmental cells. Abbreviations: FXR, farnesoid X receptors; HK, hexokinase; PKM2, pyruvate kinase M2.