Remodeling Lipids in the Transition from Chronic Liver Disease to Hepatocellular Carcinoma

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) has poor prognosis. We studied blood lipids by comparing healthy volunteers to patients with chronic liver disease (CLD), and to patients with HCC caused by viral infections. We contrasted our findings in blood to lipid alterations in liver tumor and nontumor tissue samples from HCC patients. In blood, most lipid species were found at increased levels in CLD patients compared to healthy volunteers. This trend was mostly reversed in HCC versus CLD patients. In liver tumor tissues, levels of many lipids were decreased compared to paired nontumor liver tissues. Differences in lipid levels were further defined by alterations in the degree of saturation in the fatty acyl chains. Some lipids, including free fatty acids, saturated lysophosphatidylcholines and saturated triacylglycerides, showed a continuous trend in the transition from the blood of healthy controls to CLD and HCC patients. For HCC patients, phosphatidylglycerides showed similar alterations in both blood and tissues. ABSTRACT: Hepatocellular carcinoma (HCC) is a worldwide health problem. HCC patients show a 50% mortality within two years of diagnosis. To better understand the molecular pathogenesis at the level of lipid metabolism, untargeted UPLC MS—QTOF lipidomics data were acquired from resected human HCC tissues and their paired nontumor hepatic tissues (n = 46). Blood samples of the same HCC subjects (n = 23) were compared to chronic liver disease (CLD) (n = 15) and healthy control (n = 15) blood samples. The participants were recruited from the National Liver Institute in Egypt. The lipidomics data yielded 604 identified lipids that were divided into six super classes. Five-hundred and twenty-four blood lipids were found as significantly differentiated (p < 0.05 and qFDR p < 0.1) between the three study groups. In the blood of CLD patients compared to healthy control subjects, almost all lipid classes were significantly upregulated. In CLD patients, triacylglycerides were found as the most significantly upregulated lipid class at qFDR p = 1.3 × 10(−56), followed by phosphatidylcholines at qFDR p = 3.3 × 10(−51) and plasmalogens at qFDR p = 1.8 × 10(-46). In contrast, almost all blood lipids were significantly downregulated in HCC patients compared to CLD patients, and in HCC tissues compared to nontumor hepatic tissues. Ceramides were found as the most significant lipid class (qFDR p = 1 × 10(−14)) followed by phosphatidylglycerols (qFDR p = 3 × 10(−9)), phosphatidylcholines and plasmalogens. Despite these major differences, there were also common trends in the transitions between healthy controls, CLD and HCC patients. In blood, several mostly saturated triacylglycerides showed a continued increase in the trajectory towards HCC, accompanied by reduced levels of saturated free fatty acids and saturated lysophospatidylcholines. In contrast, the largest overlaps of lipid alterations that were found in both HCC tissue and blood comparisons were decreased levels of phosphatidylglycerols and sphingolipids. This study highlights the specific impact of HCC tumors on the circulating lipids. Such data may be used to target lipid metabolism for prevention, early detection and treatment of HCC in the background of viral-related CLD etiology.