Metabolic Signature of Hepatic Fibrosis: From Individual Pathways to Systems Biology

Abstract

Hepatic fibrosis is a major cause of morbidity and mortality worldwide, as it ultimately leads to cirrhosis, which is estimated to affect up to 2% of the global population. Hepatic fibrosis is confirmed by liver biopsy, and the erroneous nature of this technique necessitates the search for noninvasive alternatives. However, current biomarker algorithms for hepatic fibrosis have many limitations. Given that the liver is the largest organ and a major metabolic hub in the body, probing the metabolic signature of hepatic fibrosis holds promise for the discovery of new markers and therapeutic targets. Regarding individual metabolic pathways, accumulating evidence shows that hepatic fibrosis leads to alterations in carbohydrate metabolism, as aerobic glycolysis is aggravated in activated hepatic stellate cells (HSCs) and the whole fibrotic liver; in amino acid metabolism, as Fischer's ratio (branched-chain amino acids/aromatic amino acids) decreases in patients with hepatic fibrosis; and in lipid metabolism, as HSCs lose vitamin A-containing lipid droplets during transdifferentiation, and cirrhotic patients have decreased serum lipids. The current review also summarizes recent findings of metabolic alterations relevant to hepatic fibrosis based on systems biology approaches, including transcriptomics, proteomics, and metabolomics in vitro, in animal models and in humans.

Keywords: Fischer’s ratio; HSC; TCA cycle; aerobic glycolysis; hepatic fibrosis; metabolomics; proteomics; transcriptomics.

Figure 1

Alterations in carbohydrate metabolism associated with hepatic fibrosis in a representative liver cell. PKM2, pyruvate kinase M2; TCA, tricarboxylic acid cycle. Upregulated metabolites, enzymes, transporters or metabolites are shown in red boxes.

Figure 2

Alterations in amino acid metabolism associated with hepatic fibrosis. BCAAs, branched-chain amino acids; ADMA, asymmetric dimethylarginine; BCKAs, branched-chain alpha-keto acids; TCA, tricarboxylic acid cycle; MAT2A, methionine adenosyltransferase 2A; SAM, intracellular S-adenosylmethionine; IDO1, indoleamine 2,3-dioxygenase 1. *: activating features only noted in cirrhotic patients with acute decompensation and with acute-on-chronic liver failure. Gray arrows indicate the involvement of all amino acids in the indicated group. Upregulated metabolites are shown in red boxes, and downregulated metabolites are shown in blue boxes.

Figure 3

Metabolic alterations in hepatitis B virus-related hepatic fibrosis. HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A; SCD, stearoyl-coenzyme A desaturase; TCA, tricarboxylic acid cycle. The gray arrow indicates the involvement of all amino acids in the indicated group. Upregulated metabolites are shown in red boxes, and downregulated metabolites are shown in blue boxes.

Figure 4

Metabolic alterations in hepatitis C virus-related hepatic fibrosis. In addition to decreasing Fisher’s ratio, hepatitis C virus-related hepatic fibrosis might lead to the impairment of mitochondrial processes, including impaired fatty acid oxidation, oxidative phosphorylation and responses to oxidative stress and reactive oxygen species. HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A; FA, fatty acids; TG, triglycerides; SM, sphingomyelin; PC, phosphatidylcholine; DCA, dicarboxylic acids; VLDL, very low-density lipoprotein-cholesterol; IDL, intermediate-density lipoprotein-cholesterol; LDL, low-density lipoprotein-cholesterol; HDL, high-density lipoprotein-cholesterol; TCA, tricarboxylic acid cycle; ROS, reactive oxygen species. Upregulated metabolites are shown in red boxes, and downregulated metabolites are shown in blue boxes.

Figure 5

Metabolic alterations in nonspecific hepatic fibrosis. HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A; FA, fatty acids; TG, triglycerides; SM, sphingomyelin; PC, phosphatidylcholine; DCA, dicarboxylic acid; TA, taurocholic acid; VLDL, very low-density lipoprotein-cholesterol; IDL, intermediate-density lipoprotein-cholesterol; LDL, low-density lipoprotein-cholesterol; HDL, high-density lipoprotein-cholesterol; TCA, tricarboxylic acid cycle. Upregulated metabolites are shown in red boxes, and downregulated metabolites are shown in blue boxes.