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

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.

The Role of Fatty Acids in Non-Alcoholic Fatty Liver Disease Progression: An Update

“…In turn, in a NASH-associated HCC mouse model, reduced levels of FFAs 18:3 n-3, 20:5 n-3, 22:6 n-3, and 18:2 n-6 were found [92]. An untargeted lipidomic analysis revealed that the blood levels of almost all lipid groups were decreased in HCC patients when compared to CLD subjects and that many specific lipid classes were upor dowregulated in HCC patients with respect to healthy controls [45]. Other research showed significantly lower levels of PCs, PSs, and PIs in the serum of HCC patients [93].…”

“…The complex lipids (which all, except steroids non-esterified with FAs, contain FA in their structure) also have diagnostic potential. Ismail et al [45] performed untargeted lipidomic analysis in blood samples, detecting more than 500 significantly different lipid species when patients with CLD were compared to healthy controls. Notably, TAG, PCs, and plasmalogens were the most significantly upregulated lipid species in the blood of CLD patients with respect to the controls.…”

“…The most common type of primary liver cancer is HCC, representing the third leading cause of cancer-related deaths worldwide [82]. Depending on the world region, the main risk factors of HCC are viral hepatitis (HCV, HBV), aflatoxin-B1 exposure [83], alcoholic-related liver disease (ARLD), and NAFLD [45,82,84]. Importantly, NAFLD is becoming the leading HCC cause in both obese patients and non-obese individuals with metabolic disorders [85].…”

“…According to many authors, the association between blood and tumor lipidomes is still little known [45]. However, certain mass spectrometry-based lipidomics studies have provided key information about the potential metabolic alterations observed in HCC patients.…”

Inhibition of Ganglioside Synthesis Suppressed Liver Cancer Cell Proliferation through Targeting Kinetochore Metaphase Signaling

“…Ceramide as the central molecule of sphingolipid metabolism has been reported to play a pro-apoptotic and anti-proliferative role in chronic liver diseases such as NASH [70], alcoholic steatohepatitis [71], and hepatic ischemia reperfusion injury [59]. Recently, the turnover from ceramide to its downstream sphingolipids such as sphigosine-1-phosphate emerge as novel diagnostic biomarkers and therapeutic targets for HCC [72].…”