NASH, Fibrosis and Hepatocellular Carcinoma: Lipid Synthesis and Glutamine/Acetate Signaling

Primary liver cancer is predicted to be the sixth most common cancer and the fourth leading cause of cancer mortality worldwide. Recent studies identified nonalcoholic fatty liver disease (NAFLD) as the underlying cause in 13–38.2% of patients with hepatocellular carcinoma unrelated to viral hepatitis and alcohol abuse. NAFLD progresses to nonalcoholic steatohepatitis (NASH), which increases the risk for the development of liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD is characterized by dysregulation of lipid metabolism. In addition, lipid metabolism is effected not only in NAFLD, but also in a broad range of chronic liver diseases and tumor development. Cancer cells manipulate a variety of metabolic pathways, including lipid metabolism, in order to build up their own cellular components. Identifying tumor dependencies on lipid metabolism would provide options for novel targeting strategies. This review article summarizes the research evidence on metabolic reprogramming and focuses on lipid metabolism in NAFLD, NASH, fibrosis, and cancer. As alternative routes of acetyl-CoA production for fatty acid synthesis, topics on glutamine and acetate metabolism are included. Further, studies on small compound inhibitors targeting lipid metabolism are discussed. Understanding reprogramming strategies in liver diseases, as well as the visualization of the metabolism reprogramming networks, could uncover novel therapeutic options.

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Lipid Metabolism in Development and Progression of Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers12061419 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1419 ◽

Cited By ~ 3

Author(s):

Moris Sangineto ◽

Rosanna Villani ◽

Francesco Cavallone ◽

Antonino Romano ◽

Domenico Loizzi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Fatty Acid ◽

Lipid Metabolism ◽

Fatty Acid Synthesis ◽

Cell Signalling ◽

Acid Synthesis ◽

Environmental Adaptation ◽

Metabolic Reprogramming ◽

Therapeutic Approaches

Metabolic reprogramming is critically involved in the development and progression of cancer. In particular, lipid metabolism has been investigated as a source of energy, micro-environmental adaptation, and cell signalling in neoplastic cells. However, the specific role of lipid metabolism dysregulation in hepatocellular carcinoma (HCC) has not been widely described yet. Alterations in fatty acid synthesis, β-oxidation, and cellular lipidic composition contribute to initiation and progression of HCC. The aim of this review is to elucidate the mechanisms by which lipid metabolism is involved in hepatocarcinogenesis and tumour adaptation to different conditions, focusing on the transcriptional aberrations with new insights in lipidomics and lipid zonation. This will help detect new putative therapeutic approaches in the second most frequent cause of cancer-related death.

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The Emerging Factors and Treatment Options for NAFLD-Related Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13153740 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3740

Author(s):

Chunye Zhang ◽

Ming Yang

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cancer ◽

Fatty Liver ◽

Early Stage ◽

Primary Liver Cancer ◽

Treatment Options ◽

Underlying Mechanism ◽

Diagnostic Methods ◽

T Cell Therapy ◽

Nonalcoholic Fatty Liver

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, followed by cholangiocarcinoma (CCA). HCC is the third most common cause of cancer death worldwide, and its incidence is rising, associated with an increased prevalence of obesity and nonalcoholic fatty liver disease (NAFLD). However, current treatment options are limited. Genetic factors and epigenetic factors, influenced by age and environment, significantly impact the initiation and progression of NAFLD-related HCC. In addition, both transcriptional factors and post-transcriptional modification are critically important for the development of HCC in the fatty liver under inflammatory and fibrotic conditions. The early diagnosis of liver cancer predicts curative treatment and longer survival. However, clinical HCC cases are commonly found in a very late stage due to the asymptomatic nature of the early stage of NAFLD-related HCC. The development of diagnostic methods and novel biomarkers, as well as the combined evaluation algorithm and artificial intelligence, support the early and precise diagnosis of NAFLD-related HCC, and timely monitoring during its progression. Treatment options for HCC and NAFLD-related HCC include immunotherapy, CAR T cell therapy, peptide treatment, bariatric surgery, anti-fibrotic treatment, and so on. Overall, the incidence of NAFLD-related HCC is increasing, and a better understanding of the underlying mechanism implicated in the progression of NAFLD-related HCC is essential for improving treatment and prognosis.

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Epithelial–Mesenchymal Transition (EMT) Induced by TGF-β in Hepatocellular Carcinoma Cells Reprograms Lipid Metabolism

International Journal of Molecular Sciences ◽

10.3390/ijms22115543 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5543

Author(s):

Jitka Soukupova ◽

Andrea Malfettone ◽

Esther Bertran ◽

María Isabel Hernández-Alvarez ◽

Irene Peñuelas-Haro ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Lipid Metabolism ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Aerobic Glycolysis ◽

Metabolic Reprogramming ◽

Migration And Invasion ◽

Metabolic Switch ◽

Mesenchymal Transition ◽

Hcc Cells

(1) Background: The transforming growth factor (TGF)-β plays a dual role in liver carcinogenesis. At early stages, it inhibits cell growth and induces apoptosis. However, TGF-β expression is high in advanced stages of hepatocellular carcinoma (HCC) and cells become resistant to TGF-β induced suppressor effects, responding to this cytokine undergoing epithelial–mesenchymal transition (EMT), which contributes to cell migration and invasion. Metabolic reprogramming has been established as a key hallmark of cancer. However, to consider metabolism as a therapeutic target in HCC, it is necessary to obtain a better understanding of how reprogramming occurs, which are the factors that regulate it, and how to identify the situation in a patient. Accordingly, in this work we aimed to analyze whether a process of full EMT induced by TGF-β in HCC cells induces metabolic reprogramming. (2) Methods: In vitro analysis in HCC cell lines, metabolomics and transcriptomics. (3) Results: Our findings indicate a differential metabolic switch in response to TGF-β when the HCC cells undergo a full EMT, which would favor lipolysis, increased transport and utilization of free fatty acids (FFA), decreased aerobic glycolysis and an increase in mitochondrial oxidative metabolism. (4) Conclusions: EMT induced by TGF-β in HCC cells reprograms lipid metabolism to facilitate the utilization of FFA and the entry of acetyl-CoA into the TCA cycle, to sustain the elevated requirements of energy linked to this process.

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Lipid metabolic Reprogramming: Role in Melanoma Progression and Therapeutic Perspectives

Cancers ◽

10.3390/cancers12113147 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3147

Author(s):

Laurence Pellerin ◽

Lorry Carrié ◽

Carine Dufau ◽

Laurence Nieto ◽

Bruno Ségui ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Tumor Cell ◽

Fatty Acid Synthase ◽

Lipid Synthesis ◽

Metabolic Reprogramming ◽

Acid Uptake ◽

Oncogenic Signaling ◽

Tumor Cell Migration ◽

Melanoma Progression

Metabolic reprogramming contributes to the pathogenesis and heterogeneity of melanoma. It is driven both by oncogenic events and the constraints imposed by a nutrient- and oxygen-scarce microenvironment. Among the most prominent metabolic reprogramming features is an increased rate of lipid synthesis. Lipids serve as a source of energy and form the structural foundation of all membranes, but have also emerged as mediators that not only impact classical oncogenic signaling pathways, but also contribute to melanoma progression. Various alterations in fatty acid metabolism have been reported and can contribute to melanoma cell aggressiveness. Elevated expression of the key lipogenic fatty acid synthase is associated with tumor cell invasion and poor prognosis. Fatty acid uptake from the surrounding microenvironment, fatty acid β-oxidation and storage also appear to play an essential role in tumor cell migration. The aim of this review is (i) to focus on the major alterations affecting lipid storage organelles and lipid metabolism. A particular attention has been paid to glycerophospholipids, sphingolipids, sterols and eicosanoids, (ii) to discuss how these metabolic dysregulations contribute to the phenotype plasticity of melanoma cells and/or melanoma aggressiveness, and (iii) to highlight therapeutic approaches targeting lipid metabolism that could be applicable for melanoma treatment.

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Small but Heavy Role: MicroRNAs in Hepatocellular Carcinoma Progression

BioMed Research International ◽

10.1155/2018/6784607 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Erbao Chen ◽

Xiaojing Xu ◽

Ruiqi Liu ◽

Tianshu Liu

Keyword(s):

Hepatocellular Carcinoma ◽

Molecular Mechanisms ◽

Human Cancer ◽

Primary Liver Cancer ◽

Tumor Development ◽

Biological Processes ◽

Regulate Gene Expression ◽

Small Noncoding Rnas ◽

Pathological Mechanism ◽

Cellular Target

Hepatocellular carcinoma (HCC), which accounts for 85–90% of primary liver cancer, is the fifth most common malignant tumor and the third leading cause of cancer-related deaths worldwide, but the pathological mechanism of HCC is still not fully elucidated. miRNAs are evolutionarily endogenous small noncoding RNAs that negatively regulate gene expression via posttranscriptional inhibition or target mRNA degradation in several diseases, especially human cancer. Therefore, discovering the roles of miRNAs is appealing to scientific researchers. Emerging evidence has shown that the aberrant expressions of numerous miRNAs are involved in many HCC biological processes. In hepatocarcinogenesis, miRNAs with dysregulated expression can exert their function as oncogenes or tumor suppressors depending on their cellular target during the cell cycle, and in tumor development, differentiation, apoptosis, angiogenesis, metastasis, and progression of the tumor microenvironment. In this review, we summarize current findings on miRNAs and assess their functions to explore the molecular mechanisms of tumor progression in HCC.

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Progesterone and Related Compounds in Hepatocellular Carcinoma: Basic and Clinical Aspects

BioMed Research International ◽

10.1155/2013/290575 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 11

Author(s):

Yao-Tsung Yeh ◽

Chien-Wei Chang ◽

Ren-Jie Wei ◽

Shen-Nien Wang

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Disease ◽

Primary Liver Cancer ◽

Clinical Aspects ◽

Protective Effects ◽

Limited Information ◽

Nonalcoholic Fatty Liver ◽

Common Cancer ◽

Liver Cancers ◽

Related Compounds

Primary liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer mortality. Hepatocellular carcinoma (HCC) accounts for 85% to 90% of primary liver cancers. Major risk factors for HCC include infection with HBV or HCV, alcoholic liver disease, and most probably nonalcoholic fatty liver disease. In general, men are two to four times more often associated with HCC than women. It can be suggested that sex hormones including progesterone may play some roles in HCC. Rather, very limited information discusses its potential involvement in HCC. This paper thus collects some recent studies of the potential involvement of progesterone and related compounds in HCC from basic and clinical aspects. In addition, two synthetic progestins, megestrol acetate (MA) and medroxyprogesterone acetate (MPA), will be discussed thoroughly. It is noted that progesterone can also serve as the precursor for androgens and estrogens produced by the gonadal and adrenal cortical tissues, while men have a higher incidence of HCC than women might be due to the stimulatory effects of androgen and the protective effects of estrogen. Eventually, this paper suggests a new insight on the associations of progesterone and related compounds with HCC development and treatment.

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LncRNAs Act as a Link between Chronic Liver Disease and Hepatocellular Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms21082883 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2883

Author(s):

Young-Ah Kim ◽

Kwan-Kyu Park ◽

Sun-Jae Lee

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Disease ◽

Chronic Liver Disease ◽

Hepatic Fibrosis ◽

Liver Diseases ◽

Molecular Mechanisms ◽

Chronic Liver ◽

Chronic Liver Diseases ◽

Nonalcoholic Fatty Liver ◽

Underlying Mechanisms

Long non-coding RNAs (lncRNAs) are emerging as important contributors to the biological processes underlying the pathophysiology of various human diseases, including hepatocellular carcinoma (HCC). However, the involvement of these molecules in chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD) and viral hepatitis, has only recently been considered in scientific research. While extensive studies on the pathogenesis of the development of HCC from hepatic fibrosis have been conducted, their regulatory molecular mechanisms are still only partially understood. The underlying mechanisms related to lncRNAs leading to HCC from chronic liver diseases and cirrhosis have not yet been entirely elucidated. Therefore, elucidating the functional roles of lncRNAs in chronic liver disease and HCC can contribute to a better understanding of the molecular mechanisms, and may help in developing novel diagnostic biomarkers and therapeutic targets for HCC, as well as in preventing the progression of chronic liver disease to HCC. Here, we comprehensively review and briefly summarize some lncRNAs that participate in both hepatic fibrosis and HCC.

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Research on the Mechanism of SIRT1/AMPK Inducing Resistance to Imatinib in K562 Cells By Inhibiting Srebp to Promote Lipid Metabolism

Blood ◽

10.1182/blood-2021-150333 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4592-4592

Author(s):

Jie Luo ◽

Dongmei Luo ◽

Hanying Liang ◽

Yaxian Tan ◽

Xiaoli Liu ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Acid Synthesis ◽

Metabolic Reprogramming ◽

Self Renewal ◽

Imatinib Resistant ◽

Sirt1 Inhibitor ◽

Low Glucose

Abstract Background Leukemia stem cells (LSC) have the characteristics of independent of BCR-ABL kinase activity and metabolic reprogramming to support self-renewal. They are the root cause of the occurrence of chronic myeloid leukemia (CML), mediating TKI resistance and leading to clonal evolution. LSC self-renewal depends on the activity of SIRT1, the enhanced of SIRT1 induces LSC mitochondrial metabolic reprogramming. Studies have shown that SIRT1 and abnormally activated lipid metabolism are important reasons for inducing CML resistance to imatinib. Objective Study the mechanism of SIRT1 regulating lipid metabolism and intervention strategies under imatinib therapy. Method Liquid chromatography coupled with mass spectrometry (LC-MS) were used to analysis the lipid metabolism in imatinib-resistant CML cell line K562-R under low-glucose conditions. RT-qPCR and Western blot were used to detect the key enzymes related to lipid metabolism, and the SIRT1 inhibitor TV-6 was given to study the regulation mechanism of SIRT1 on lipid metabolism. Result Firstly, we found that the glycolysis/gluconeogenesis pathway and fatty acid metabolism were abnormal in K562-R cells by metabolomics, compared with normal culture conditions, the expression of SIRT1 and AMPK were significantly increased, the expression of fatty acid synthesis-related genes (SREBP, FASN, ACC, SCD1) was significantly reduced, and the fatty acid β oxidation rate-limiting enzyme CPT-1 is significantly increased inK562-R cells under low-glucose conditions. Therefore, in the low-glucose environment, the expression of the above genes was reversed after the application of the SIRT1 inhibitor TV-6. Conclusion K562-R imatinib-resistant cells can down-regulate the expression of SREBP through up-regulated SIRT1/AMPK pathway under low-glucose conditions, thereby inhibiting the expression of transcription factors involved in lipogenesis, reducing fatty acid synthesis, and providing the imatinib-resistant cells with the energy which required for proliferation. Keyword Chronic myeloid leukemia; Metabolomics; Lipid metabolism; SIRT1/AMPK Disclosures No relevant conflicts of interest to declare.

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Circadian lipid synthesis in brown fat maintains murine body temperature during chronic cold

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1909883116 ◽

2019 ◽

Vol 116 (37) ◽

pp. 18691-18699 ◽

Cited By ~ 2

Author(s):

Marine Adlanmerini ◽

Bryce J. Carpenter ◽

Jarrett R. Remsberg ◽

Yann Aubert ◽

Lindsey C. Peed ◽

...

Keyword(s):

Lipid Metabolism ◽

Body Temperature ◽

Cold Exposure ◽

De Novo ◽

Lipid Synthesis ◽

Acid Synthesis ◽

High Amplitude ◽

De Novo Lipogenesis ◽

Brown Adipose ◽

The Impact

Ambient temperature influences the molecular clock and lipid metabolism, but the impact of chronic cold exposure on circadian lipid metabolism in thermogenic brown adipose tissue (BAT) has not been studied. Here we show that during chronic cold exposure (1 wk at 4 °C), genes controlling de novo lipogenesis (DNL) includingSrebp1, the master transcriptional regulator of DNL, acquired high-amplitude circadian rhythms in thermogenic BAT. These conditions activated mechanistic target of rapamycin 1 (mTORC1), an inducer ofSrebp1expression, and engaged circadian transcriptional repressors REV-ERBα and β as rhythmic regulators ofSrebp1in BAT. SREBP was required in BAT for the thermogenic response to norepinephrine, and depletion of SREBP prevented maintenance of body temperature both during circadian cycles as well as during fasting of chronically cold mice. By contrast, deletion of REV-ERBα and β in BAT allowed mice to maintain their body temperature in chronic cold. Thus, the environmental challenge of prolonged noncircadian exposure to cold temperature induces circadian induction of SREBP1 that drives fuel synthesis in BAT and is necessary to maintain circadian body temperature during chronic cold exposure. The requirement for BAT fatty acid synthesis has broad implications for adaptation to cold.

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Metabolomic and Lipidomic Biomarkers for Premalignant Liver Disease Diagnosis and Therapy

Metabolites ◽

10.3390/metabo10020050 ◽

2020 ◽

Vol 10 (2) ◽

pp. 50 ◽

Cited By ~ 7

Author(s):

Diren Beyoğlu ◽

Jeffrey R. Idle

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Disease ◽

Liver Diseases ◽

Large Body ◽

Disease Diagnosis ◽

Early Prediction ◽

Phenyllactic Acid ◽

Nonalcoholic Fatty Liver ◽

Major Criterion ◽

Liver Disease Diagnosis

In recent years, there has been a plethora of attempts to discover biomarkers that are more reliable than α-fetoprotein for the early prediction and prognosis of hepatocellular carcinoma (HCC). Efforts have involved such fields as genomics, transcriptomics, epigenetics, microRNA, exosomes, proteomics, glycoproteomics, and metabolomics. HCC arises against a background of inflammation, steatosis, and cirrhosis, due mainly to hepatic insults caused by alcohol abuse, hepatitis B and C virus infection, adiposity, and diabetes. Metabolomics offers an opportunity, without recourse to liver biopsy, to discover biomarkers for premalignant liver disease, thereby alerting the potential of impending HCC. We have reviewed metabolomic studies in alcoholic liver disease (ALD), cholestasis, fibrosis, cirrhosis, nonalcoholic fatty liver (NAFL), and nonalcoholic steatohepatitis (NASH). Specificity was our major criterion in proposing clinical evaluation of indole-3-lactic acid, phenyllactic acid, N-lauroylglycine, decatrienoate, N-acetyltaurine for ALD, urinary sulfated bile acids for cholestasis, cervonoyl ethanolamide for fibrosis, 16α-hydroxyestrone for cirrhosis, and the pattern of acyl carnitines for NAFL and NASH. These examples derive from a large body of published metabolomic observations in various liver diseases in adults, adolescents, and children, together with animal models. Many other options have been tabulated. Metabolomic biomarkers for premalignant liver disease may help reduce the incidence of HCC.

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