Lipid Metabolism In Hepatocellular Carcinoma Research Articles

Aberrant Lipid Metabolism in Hepatocellular Carcinoma Revealed by Liver Lipidomics.

Background: The aim of this study was to characterize the disorder of lipid metabolism in hepatocellular carcinoma (HCC). HCC is a worldwide disease. The research into the disorder of lipid metabolism in HCC is very limited. Study of lipid metabolism in liver cancer tissue may have the potential to provide new insight into HCC mechanisms. Methods: A lipidomics study of HCC based on Ultra high performance liquid chromatography-electronic spray ionization-QTOF mass spectrometer (UPLC-ESI-QTOF MS) and Matrix assisted laser desorption ionization-fourier transform ion cyclotron resonance mass spectrometer (MALDI-FTICR MS) was performed. Results: Triacylglycerols (TAGs) with the number of double bond (DB) > 2 (except 56:5 and 56:4 TAG) were significantly down-regulated; conversely, others (except 52:2 TAG) were greatly up-regulated in HCC tissues. Moreover, the more serious the disease was, the higher the saturated TAG concentration and the lower the polyunsaturated TAG concentration were in HCC tissues. The phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI) were altered in a certain way. Sphingomyelin (SM) was up-regulated and ceramide (Cer) were down-regulated in HCC tissues. Conclusions: To our knowledge, this is the first such report showing a unique trend of TAG, PC, PE and PI. The use of polyunsaturated fatty acids, like eicosapentanoic and docosahexanoic acid, as supplementation, proposed for the treatment of Non-alcoholic steatohepatitis (NASH), may also be effective for the treatment of HCC.

Abstract 2516: Pokemon functions as a metabolic oncoprotein integrating glucose & lipid metabolism in hepatocellular carcinoma

Abstract Pokemon (also known as FBI-1 or LRF) is a proto-oncogene encoded by ZBTB7A gene. It functions as a transcription factor, playing important roles in embryonic development, cell differentiation and neoplasia. Pokemon is abnormally expressed in hepatocellular carcinoma (HCC) and may contribute to the metabolic homeostasis of HCC cells, but the mechanism of action remains to be fully understood. This study demonstrated that Pokemon may integrate glycolysis and lipid metabolism in hepatocellular carcinogenesis. Our data showed that Pokemon was upregulated in HCC cell lines and clinical samples. Ectopic expression of Pokemon stimulated HCC cell growth and proliferation in culture and tumorigenesis in nude mice. Lipid metabolomic analysis by LC/MS exhibited that in HCC cells lipogenesis was positively correlated with Pokemon expression levels, and targeted expression of Pokemon in HCC cells promoted the flux of radiolabeled glucose to lipids, including membrane phospholipids, through the aerobic glycolysis-acetyl-CoA metabolic stream. Mechanistic studies revealed that Pokemon stimulated glycolysis through activation of PKA and its mediated Raf/c-Myc pathway. In the tested HCC cells, Pokemon activated fatty acid synthase (FASN) and suppressed AMPK, an inhibitor of acetyl-CoA carboxylase α (ACC-α), stimulating fatty acid and lipid synthesis. Together our results suggest that Pokemon correlates glycolysis and lipid synthesis and thus promotes lipogenesis and hepatocellular tumorigenesis. Note: This abstract was not presented at the meeting. Citation Format: Yibao Jin, Shangfu Li, Deliang Cao, Dan Gao, Hongxia Liu, Feng Liu, Tiejie Wang, Yuyang Jiang. Pokemon functions as a metabolic oncoprotein integrating glucose & lipid metabolism in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2516. doi:10.1158/1538-7445.AM2017-2516

TIP30 regulates lipid metabolism in hepatocellular carcinoma by regulating SREBP1 through the Akt/mTOR signaling pathway

Lipid reprogramming has been considered as a crucial characteristic in hepatocellular carcinoma (HCC) initiation and progression. However, detailed molecular mechanisms have yet to be clearly defined. Here, we examined the effects of tumor suppressor TIP30 on the regulation of HCC lipid metabolism. We found that decreased TIP30 expression leads to elevated fatty acid synthesis and enhanced levels of lipogenic enzymes SCD and FASN in HCC cells. Moreover, SREBP1 is one of the key transcription factors regulating liver lipid metabolism, and TIP30 deficiency significantly increased SREBP1 expression and nuclear accumulation. Small interfering RNAs targeting SREBP1 could reverse fatty acid synthesis induced by TIP30 deficiency. Furthermore, downregulating TIP30 activated the Akt/mTOR signaling pathway to upregulate SREBP1 expression, which promoted lipid metabolism by activating gene transcription of lipogenesis, including fasn and scd. We also showed that TIP30 deficiency-regulated lipid metabolism promoted proliferation of HCC cells. Clinically, our data revealed that TIP30 expression significantly correlated with SREBP1 in patients with HCC and that a combination of TIP30 and SREBP1 is a powerful predictor of HCC prognosis. Together, our data suggested a novel function of TIP30 in HCC progression and indicate that TIP30 regulation of SREBP1 may represent a novel target for HCC treatment.

Aspirin suppresses the abnormal lipid metabolism in liver cancer cells via disrupting an NFκB-ACSL1 signaling

Abnormal lipid metabolism is a hallmark of tumorigenesis. Hence, the alterations of metabolism enhance the development of hepatocellular carcinoma (HCC). Aspirin is able to inhibit the growth of cancers through targeting nuclear factor κB (NF-κB). However, the role of aspirin in disrupting abnormal lipid metabolism in HCC remains poorly understood. In this study, we report that aspirin can suppress the abnormal lipid metabolism of HCC cells through inhibiting acyl-CoA synthetase long-chain family member 1 (ACSL1), a lipid metabolism-related enzyme. Interestingly, oil red O staining showed that aspirin suppressed lipogenesis in HepG2 cells and Huh7 cells in a dose-dependent manner. In addition, aspirin attenuated the levels of triglyceride and cholesterol in the cells, respectively. Strikingly, we identified that aspirin was able to down-regulate ACSL1 at the levels of mRNA and protein. Moreover, we validated that aspirin decreased the nuclear levels of NF-κB in HepG2 cells. Mechanically, PDTC, an inhibitor of NF-κB, could down-regulate ACSL1 at the levels of mRNA and protein in the cells. Functionally, PDTC reduced the levels of lipid droplets, triglyceride and cholesterol in HepG2 cells. Thus, we conclude that aspirin suppresses the abnormal lipid metabolism in HCC cells via disrupting an NFκB-ACSL1 signaling. Our finding provides new insights into the mechanism by which aspirin inhibits abnormal lipid metabolism of HCC. Therapeutically, aspirin is potentially available for HCC through controlling abnormal lipid metabolism.

Long noncoding RNA HULC modulates abnormal lipid metabolism in hepatoma cells through an miR-9-mediated RXRA signaling pathway.

HULC is a long noncoding RNA overexpressed in hepatocellular carcinoma (HCC), but its functional contributions in this setting have not been determined. In this study, we explored the hypothesis that HULC contributes to malignant development by supporting abnormal lipid metabolism in hepatoma cells. HULC modulated the deregulation of lipid metabolism in HCC by activating the acyl-CoA synthetase subunit ACSL1. Immunohistochemical analysis of tissue microarrays revealed that approximately 77% (180/233) of HCC tissues were positive for ACSL1. Moreover, HULC mRNA levels correlated positively with ACSL1 levels in 60 HCC cases according to real-time PCR analysis. Mechanistic investigations showed that HULC upregulated the transcriptional factor PPARA, which activated the ACSL1 promoter in hepatoma cells. HULC also suppressed miR-9 targeting of PPARA mRNA by eliciting methylation of CpG islands in the miR-9 promoter. We documented the ability of HULC to promote lipogenesis, thereby stimulating accumulation of intracellular triglycerides and cholesterol in vitro and in vivo. Strikingly, ACSL1 overexpression that generates cholesterol was sufficient to enhance the proliferation of hepatoma cells. Further, cholesterol addition was sufficient to upregulate HULC expression through a positive feedback loop involving the retinoid receptor RXRA, which activated the HULC promoter. Overall, we concluded that HULC functions as an oncogene in hepatoma cells, acting mechanistically by deregulating lipid metabolism through a signaling pathway involving miR-9, PPARA, and ACSL1 that is reinforced by a feed-forward pathway involving cholesterol and RXRA to drive HULC signaling.

Abstract 4329: Lipid droplets and associated proteins in hepatocellular carcinoma tumour cells

Abstract Introduction: Fatty acids are a major source of energy but can be toxic. Cells avoid cytotoxicity by esterifying fatty acids into neutral lipids and packaging them into lipid droplets (LDs). The perilipins (PLINs) are a family of the 5 most abundant LD-associated proteins coating and regulating the LDs1. Numerous studies have shown links between deregulated lipid metabolism and a wide variety of diseases, including diabetes, obesity, and cancer2. Hepatocellular carcinoma (HCC) arising from a background of fatty liver disease accounts for 15%-50% of HCC cases in the United States3. As it has been proposed that an imbalance of lipid composition may disrupt cellular functions and lead to the onset of cancer4, and as it was found that deregulated cancer pathways such as the mTOR pathway lead to increased lipogenesis5, it is crucial to consider the impact of the expression levels of specific PLINs in the development and progression of HCC. We hypothesize that understanding the PLIN expression and lipid profile of the tumor and the target organ will allow us to further understand the role of lipid metabolism in HCC. To address this we are manipulating PLIN expression levels in an in vitro system, and using human samples obtained through the Liver Disease Biobank (Dr. Metrakos: IRB approved protocol) to evaluate PLIN function ex vivo. Preliminary Results: Knock-down of PLINs - Lentiviral constructs containing shRNA sequences for RNA-interference of PLINs 2, 3, and 5 (which were found to be most highly expressed in HCC6) were generated. Knock-Down (KD) lines of PLINs 2 and 3 were successfully created in HepG2. The PLIN 5 KD line has proved difficult to identify due to antibody specificity. Understanding the role of PLINs - Assessment of cell proliferation in PLIN 2 and 3 KD lines has shown a decrease in growth compared to the Scrambled shRNA control, with no significant difference in proliferation between PLIN 2 and 3 KD lines. When challenged with Oleic Acid, proliferation is further reduced compared to the control line, and PLIN 3 KD cell growth is comparably less than that of PLIN 2 KD cells. Next steps: Having identified a correlation between PLIN 2 and 3 expression levels and cancer cell proliferation, we are now using the Fluorescent Activated Cell Sorting system to further characterize these cell lines. We are also analyzing human blood and tissue (cancerous and normal) to broaden our understanding of the impact of the PLINs in cancer development and progression. These studies may allow for potential targeting of PLINs in cancer therapy, and as biomarkers for liver disease.

MiR-205 modulates abnormal lipid metabolism of hepatoma cells via targeting acyl-CoA synthetase long-chain family member 1 (ACSL1) mRNA

The abnormal lipid metabolism is considered as a hallmarker of tumorigenesis. Liver is the central organ for metabolic homeostasis. Hence, the development of hepatocellular carcinoma (HCC) always exhibits alterations of metabolism. MicroRNAs emerge as key post-transcriptional modulators of gene expression in physiologic and pathologic states. Here, we aim to explore the mechanism of abnormal lipid metabolism of hepatoma cells. Previously, our group reported that miR-205 as a tumor suppressor was down-regulated in HCC. Therefore, we supposed that miR-205 might be involved in the event. Interestingly, in this study we uncover that miR-205 deregulates lipid metabolism in HCC through targeting acyl-CoA synthetase long-chain family member 1 (ACSL1) mRNA, which is an important and abundant lipid metabolism enzyme in liver. We identified that miR-205 was able to down-regulate ACSL1 via targeting its 3′UTR in the cells. Oil red O staining showed that miR-205 disordered the lipogenesis in hepatoma cells and anti-miR-205 resulted in the accumulation of triglyceride in the cells depending on ACSL1. Moreover, we validated that the low levels of miR-205 were negatively related to high levels of ACSL1 in clinical HCC tissues. The expression levels of ACSL1 and its metabolite triglyceride levels were remarkably increased in hepatitis B virus X protein (HBx)-induced liver cancer tissues from the HBx transgenic mice model. Thus, we conclude that miR-205-targeted ACSL1 may contribute to the abnormal lipid metabolism of liver cancer. Our finding provides new insights into the dysregulation of lipid metabolism in HCC mediated by miR-205 targeting ACSL1 mRNA.