Abstract
Liver cancer is one of the leading causes of death worldwide due to late diagnosis and scarcity of treatment options. The major risk factor for liver cancer is cirrhosis with the underlying causes of cirrhosis being viral infection (hepatitis B or C), metabolic deregulation (Non-alcoholic fatty liver disease (NAFLD) in the presence of obesity and diabetes), alcohol or cholestatic disorders. Lysophosphatidic acid (LPA) is a bioactive phospholipid with numerous effects, most of them compatible with the hallmarks of cancer (proliferation, migration, invasion, survival, evasion of apoptosis, deregulated metabolism, neoangiogenesis, etc.). Autotaxin (ATX) is the enzyme responsible for the bulk of extracellular LPA production, and together with LPA signaling is involved in chronic inflammatory diseases, fibrosis and cancer. This review discusses the most important findings and the mechanisms related to ATX/LPA/LPAR involvement on metabolic, viral and cholestatic liver disorders and their progression to liver cancer in the context of human patients and mouse models. It focuses on the role of ATX/LPA in NAFLD development and its progression to liver cancer as NAFLD has an increasing incidence which is associated with the increasing incidence of liver cancer. Bearing in mind that adipose tissue accounts for the largest amount of LPA production, many studies have implicated LPA in adipose tissue metabolism and inflammation, liver steatosis, insulin resistance, glucose intolerance and lipogenesis. At the same time, LPA and ATX play crucial roles in fibrotic diseases. Given that hepatocellular carcinoma (HCC) is usually developed on the background of liver fibrosis, therapies that both delay the progression of fibrosis and prevent its development to malignancy would be very promising. Therefore, ATX/LPA signaling appears as an attractive therapeutic target as evidenced by the fact that it is involved in both liver fibrosis progression and liver cancer development.
Highlights
Liver cancer is one of the leading causes of death worldwide due to late diagnosis and scarcity of treatment options
The implication of Lysophosphatidic acid (LPA) signaling in chronic inflammation has been illustrated in numerous chronic inflammatory diseases, such as idiopathic pulmonary fibrosis (IPF), a chronic, interstitial lung disease caused by aberrant wound healing
Data mining analysis has shown that even though the mRNA levels of all LPA receptors (LPARs) (LPAR1–6) and ATX are increased in the liver upon chronic liver diseases of different etiology and in the stage of liver cirrhosis, in the context of hepatocellular carcinoma (HCC) only ATX, LPAR2 and LPAR6 are increased in the liver tumor compared to non-tumoral areas [152]
Summary
The main precursor of LPA is LPC, while other lysophospholipids such as lysophosphatidylethanolamine and lysophosphatidylserine can serve as LPA precursors. LPC is synthesized by phospholipases A2 (PLA2 ) employing membrane or extracellular phosphatidylcholine (PC) as a substrate, while, simultaneously, free fatty acids (FFA) are produced (Figure 1). The enzyme responsible for the extracellular hydrolysis of LPC, and the other lysophospholipids, to LPA is Autotaxin (ATX), a secreted glycoprotein with lysophospholipase D (lysoPLD) activity [14]. Apart from ATX, other possible LPA synthetic pathways exist [1], such as LPA generation from phosphatidic acid (PA) (Figure 1). LPA is an intermediate metabolite in de novo lipogenesis (DNL), both in adipose tissue and in liver In this pathway, LPA is generated upon the acylation of glycerol-3-phosphate by glycerol-3-phosphate acyltransferase (GPAT) using acyl-CoA as a lipid donor (Figure 1) [34]. Cancers 2019, 11, xof hepatic cells ([34] and references therein)
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