Lipid alterations in chronic liver disease and liver cancer

Abstract

Lipids are a complex and diverse group of molecules with crucial roles in many physiological processes, as well as in the onset, progression, and maintenance of cancers. Fatty acids and cholesterol are the building blocks of lipids, orchestrating these crucial metabolic processes. In the liver, lipid alterations are prevalent as a cause and consequence of chronic hepatitis B and C virus infections, alcoholic hepatitis, and non-alcoholic fatty liver disease and steatohepatitis. Recent developments in lipidomics have also revealed that dynamic changes in triacylglycerols, phospholipids, sphingolipids, ceramides, fatty acids, and cholesterol are involved in the development and progression of primary liver cancer. Accordingly, the transcriptional landscape of lipid metabolism suggests a carcinogenic role of increasing fatty acids and sterol synthesis. However, limited mechanistic insights into the complex nature of the hepatic lipidome have so far hindered the development of effective therapies.

Keywords: ACC, acetyl-CoA carboxylase; ACLY, ATP citrate lyase; ALD, alcohol-related liver disease; BAs, bile acids; CCA, cholangiocarcinoma; CPT, carnitine palmitoyltransferase; Cer, ceramide(s); DNL, de novo lipogenesis; ELOV1-6, elongation of very-long-chain fatty acids; FA, fatty acid; FABP, fatty acid-binding protein; FADS2, fatty acid desaturase 2; FAO, fatty acid oxidation; FASN, fatty acid synthase; FXR, farnesoid X receptor; HCC, hepatocellular carcinoma; HMGCR, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase; HSCs, hepatic stellate cells; LA, linoleic acid; LPC, lysophosphatidylcholine; LXR, liver X receptor; MUFA, monounsaturated fatty acid; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; Non-alcoholic fatty liver disease; PC, phosphatidylcholine; PPARs, peroxisome proliferator-activated receptors; PSC, primary sclerosing cholangitis; PUFA, polyunsaturated fatty acid; S1P, sphingosine-1-phosphate; SCD, stearoyl-CoA desaturase; SE, sterol esters; SFA, saturated fatty acid; SM, sphingomyelin; SREBP, sterol regulatory element-binding protein; TERT, telomerase reverse transcriptase; TG, triglycerides; TLR, Toll-like receptor; cholangiocarcinoma; hepatocellular carcinoma; lipidomics; metabolomics.

Fig. 1

Simplified representation of the major metabolic pathways responsible for the uptake, transport, synthesis, and utilisation of lipids in the liver. FA and cholesterol are the building blocks of most complex lipids. They can either be synthesised (orange arrows) via DNL (up to 25% of FA pool) and cholesterol synthesis (up to 80% of cholesterol pool) or they can be taken directly from the circulation. FA are subjected to FAO (red arrow) via a series of catabolic reactions, which are carried out in the mitochondria to generate ATP or used to form complex lipids. Lipids play structural (blue), signalling (green) or energy storage (yellow) functions. BA, bile acids; Cer, ceramides; Chol, cholesterol; ChoE, cholesterol esters; DG, diglyceride; DNL, de novo lipogenesis; FAO, fatty acid oxidation; FFA, free fatty acids; LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; LPI, lysophosphoinositide; LPS, lysophosphatidylserine; MUFA, monounsaturated FA; PA, phosphatidate; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PI, phosphoinositide; PS, phosphatidylserine; PUFA, polyunsaturated FA; S1P, sphingosine-1-phosphate; SM, sphingomyelin; TG, triglyceride.

Fig. 2

The interplay between lipid metabolism and oncogene pathways that leads to tumorigenesis in the liver. Various lipids influence and are influenced by the recurrently deregulated oncogenic pathways, p53, RAS/MAPK, PI3K/AKT/mTOR signalling axis, Wnt/β-catenin signalling axis, TGF-β signalling axis and myc and TAZ/YAP pathways to cause hepatocarcinogenesis. The inhibited genes are marked with (⊥) and activated with (↓). The recurrent molecular alterations in oncogenes are marked with (∗). CL, cardiolipin; CTGF, connective tissue growth factor; DNL, de novo lipogenesis; FA, fatty acid; GlcCer, glucosylceramide; mTOR, mammalian target of rapamycin; NPC1, NPC intracellular cholesterol transporter 1; PI3K, phosphoinositide 3-kinase; PDK1, phosphoinositide-dependent protein kinase 1; S1P, sphingosine-1-phosphate; SL, sphingolipid; TG, triglycerides; TGF-β, transforming growth factor-β; YAP, Yes-associated protein.

Fig. 3

Transcriptionally deregulated lipidomic processes are different in HCC compared to CCA. The alteration in gene expression profiles of tumour vs. surrounding tissue in HCC (first arrow) and CCA (second arrow). The upregulated genes are marked with red ↑, and downregulated with ↓. ACLY, acetyl-CoA by ATP citrate lyase; ACC, acetyl-CoA carboxylase; BA, bile acids; CCA, cholangiocarcinoma; Chol, cholesterol; DGAT1/2, diglyceride acyltransferase 1 and 2; DNL, de novo lipogenesis; ELOVLs, elongation of very-long-chain fatty acids; FADS2, fatty acid desaturase 2; FAO, fatty acid oxidation; FASN, fatty acid synthase; FATPs, fatty acid transport proteins; FFA, free fatty acids; HCC, hepatocellular carcinoma; HMGCR, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase; LPL, lipoprotein lipase; MUFA, monounsaturated FA; PUFA, polyunsaturated FA; SCD, stearoyl-CoA desaturase; SQLE, squalene epoxidase; TG, triglyceride.

Fig. 4

Outline of the lipidomic alterations in liver cancer progression. Progression from the normal liver through chronic liver disease (hepatic steatosis to NASH) and into primary liver cancers. Oncogenic pathways activated by a change in different metabolic classes (SFA; MUFA; S1P; TG; BA; Chol) during neoplastic onset. Activation of DNL and p53-mediated inactivation of FAO. BA, bile acid; Chol, cholesterol; DNL, de novo lipogenesis; FAO, fatty acid oxidation; MUFA, monounsaturated fatty acid; NASH, non-alcoholic steatohepatitis; S1P, sphingosine-1-phosphate; SFA, saturated fatty acid; TG, triglyceride.