Role of Metabolism in Hepatic Stellate Cell Activation and Fibrogenesis

Abstract

Activation of hepatic stellate cell (HSC) involves the transition from a quiescent to a proliferative, migratory, and fibrogenic phenotype (i.e., myofibroblast), which is characteristic of liver fibrogenesis. Multiple cellular and molecular signals which contribute to HSC activation have been identified. This review specially focuses on the metabolic changes which impact on HSC activation and fibrogenesis.

Keywords: fibroblast; glutaminolysis; glycolysis; liver fibrosis; metabolic.

FIGURE 1

Activation of hepatic stellate cells (HSCs) through induction of aerobic glycolysis (Warburg effect). The transformation of glucose to lactate during HSC activation even when amounts of oxygen are available, leads to accumulation of intracellular lactate. Mitochondria may remain functional and some oxidative phosphorylation continue in cells. Aerobic glycolysis is less efficient than oxidative phosphorylation for generating adenosine 5′-triphosphate (ATP), which suggests that metabolites (for example, lactate) generated by aerobic glycolysis may have a more important role in the regulation of cellular functions than simply energy production during HSC activation.

FIGURE 2

Biochemical reactions in glutaminolysis. Glutaminolysis is the conversion of glutamine (Gln) to α-ketoglutarate (α-KG) and consists of two reactions: the first reaction is catalyzed by the glutaminase (GLS), which converts Gln into glutamate (Glu) by losing an amino group; the second step consists of the conversion of Glu to α-KG, a critical intermediate in the tricarboxylic acid (TCA) cycle, which is catalyzed by glutamate dehydrogenase or aminotransferases.

FIGURE 3

Two different metabolic pools of lipid droplets (LDs) in activated HSCs. The “original”/“old” LDs (depicted in brown), are located predominately round the nucleus, and contains predominantly triacylglycerol (TAG) and retinyl ester (RE), as well as retinol acyltransferase (LRAT). Lysosomal acid lipase (LAL/Lipa) is involved in the degradation of the “original”/“old” LDs in the lysosome during activation. The “new” LDs (depicted in yellow) which are smaller than “old” LDs, contain less REs but are enriched in TAGs, and are located in the periphery of the cells. Diacylglycerol O-acyltransferase 1 (DGAT1) and adipose triglyceride lipase (ATGL) are involved in the synthesis and breakdown of these newly synthesized TAGs, respectively.

FIGURE 4

Signaling pathways involved in free cholesterol (FC) accumulation mediated HSC activation. Downregulation of Niemann–Pick type C2 protein (NPC2) results in FC accumulation and enhances platelet-derived growth factor BB (PDGF-BB)-induced HSC proliferation by extracellular signal-regulated kinases (ERKs), p38, c-Jun N-terminal kinases (JNK), and protein kinase B (AKT) phosphorylation. In addition, the mitochondrial respiration function is impaired. FC accumulation also increases Toll-like receptor 4 protein (TLR4) expression, thereby sensitizing cells to TGF-β-induced activation through down-regulation of TGFβ-pseudoreceptor Bambi. Along with HSC activation, subsequent upregulation of both sterol regulatory element-binding protein 2 (SREBP2) and miR-33a signaling leads to further FC accumulation and exaggerates liver fibrosis in a positive feedforward loop.

FIGURE 5

Role of succinate in HSC activation. Succinate, an intermediate in the TCA cycle, functions as a paracrine signal between hepatocytes and HSCs, through binding and activation of its cognate G protein-coupled receptor 91 (GPR91), which resulted in upregulation of fibrogenic markers alpha-smooth muscle actin (α-SMA), transforming growth factor β (TGF-β), and collagen type I. Sirtuin 3 (SIRT3), a NAD+-dependent protein deacetylase, predominantly localized in the mitochondrial matrix, is a key regulator of dehydrogenase (SDH) activity. The SIRT3-SDH-GPR91 axis regulates HSC activation. Repression of succinate-GPR91 signaling by LY2405319, an analog of fibroblast growth factor 21 (FGF21), as well as metformin inhibits HSC activation.