Role of lactate and lactate metabolism in liver diseases (Review)

Abstract

Lactate is a byproduct of glycolysis, and before the Warburg effect was revealed (in which glucose can be fermented in the presence of oxygen to produce lactate) it was considered a metabolic waste product. At present, lactate is not only recognized as a metabolic substrate that provides energy, but also as a signaling molecule that regulates cellular functions under pathophysiological conditions. Lactylation, a post‑translational modification, is involved in the development of various diseases, including inflammation and tumors. Liver disease is a major health challenge worldwide. In normal liver, there is a net lactate uptake caused by gluconeogenesis, exhibiting a higher net lactate clearance rate compared with any other organ. Therefore, abnormalities of lactate and lactate metabolism lead to the development of liver disease, and lactate and lactate metabolism‑related genes can be used for predicting the prognosis of liver disease. Targeting lactate production, regulating lactate transport and modulating lactylation may be potential treatment approaches for liver disease. However, currently there is not a systematic review that summarizes the role of lactate and lactate metabolism in liver diseases. In the present review, the role of lactate and lactate metabolism in liver diseases including liver fibrosis, non‑alcoholic fatty liver disease, acute liver failure and hepatocellular carcinoma was summarized with the aim to provide insights for future research.

Keywords: acute liver failure; hepatocellular carcinoma; lactate; lactate metabolism; non‑alcoholic fatty liver disease.

Figure 1

Main production pathway of lactate. In the cytoplasm, glucose is converted to pyruvate through a series of catalytic reactions. Under normal oxygenation, pyruvate is transported to the mitochondria for the TCA cycle. However, under hypoxic conditions, pyruvate is catalyzed by LDHA to lactate. Glutamate is converted to α-ketoglutarate by GLUD in the mitochondria. Subsequently, α-KG is converted to malate, which is then transported out of the mitochondria and oxidized to pyruvate in the cellular matrix. Finally, lactic acid is produced by the action of LDHA. GLUT1/4, glucose transporter 1/4; HK2, hexokinase 2; PDH, pyruvate dehydrogenase; LDHA/B, lactate dehydrogenase A/B; TCA, tricarboxylic acid; GLUD, glutamate dehydrogenase; α-KG, α-ketoglutarate.

Figure 2

Role of lactate in liver diseases. In the liver, lactate is transported into and out of cells via MCT1 and MCT4, respectively. The increase of lactate in the liver can promote liver fibrosis through the activation of HSCs. HK2 induces histone lactylation at H3K181a to promote lactate production, which induces liver fibrosis. PCAF inhibits the activity of LDHB by acting at the K82 site of LDHB to promote acetylation, thereby inhibiting lactate clearance and thus contributing to the development of NAFLD. D-lactate inhibits the PI3K/AKT1/STAT6/PPARγ pathway by interacting with TLR2/TLR9, which activates AKT2/STAT1/NF-κB to promote the transformation of M2 Mø to M1 Mø. In HCC, lactate promotes PD-1 expression thereby increasing drug resistance. However, β-HB inhibits lactate production, and suppresses HCC proliferation and migration by inhibiting the B-Raf/MAPK pathway and EMT, as well as increasing the drug sensitivity of HCC. SIRT3 induces the delactylation of CCNE2 to inhibit the development of HCC. The nano particle formulation, DL@ NP-M-M2pep, acts on macrophages to inhibit MDSCs, Tregs and tumor growth. Another nanoformulation, LOX-MnO2 @Gel, reduces the lactate levels to restore the intratumoral function of CTLs, inhibit Tregs and reduce M2 Mø. MCT1/4, monocarboxylate transporter 1/4; HSCs, hepatic stellate cells; HK2, hexokinase 2; PCAF, P300/cyclic AMP response element-binding protein-associated factor; LDHB, lactate dehydrogenase B; NAFLD, non-alcoholic fatty liver disease; TLR2/9, Toll-like receptor; M2 Mø, M2 macrophages; M1 Mø, M1 macrophages; HCC, hepatocellular carcinoma; PD-1, programmed death-1; β-HB, β-hydroxybutyrate; EMT, epithelial-mesenchymal transition; SIRT3, sirtuin 3; CCNE2, cyclin E2; MDSCs, myeloid-derived suppressor cells; Tregs, regulatory T cells; CTLs, cytotoxic T lymphocytes; 2-DG, 2-deoxy-D-glucose; AC, acetylated; NASH, non-alcoholic steatohepatitis; DL, D-lactate; PPARγ, peroxisome proliferator-activated receptor γ; P, phosphorylated.