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β-catenin oncogenic activation rewires fatty acid catabolism to fuel hepatocellular carcinoma
  1. Alexandra Montagner1,
  2. Laurent Le Cam2,3,
  3. Hervé Guillou4
  1. 1 Institut National de la Santé et de la Recherche Médicale (INSERM), U1048 and Université Toulouse III, I2MC, Toulouse, Midi-Pyrénées, France
  2. 2 IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, Languedoc-Roussillon, France
  3. 3 Equipe Labellisée Ligue Contre le Cancer, Montpellier, France
  4. 4 Toxalim, Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
  1. Correspondence to Dr Hervé Guillou, Integrative Toxicology and Metabolism, INRA ToxAlim, Toulouse 31027, France; herve.guillou{at}toulouse.inra.fr

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Liver cancer is a major public health issue and generally considered an inflammation-related cancer developing in response to genotoxic exposure or in patients with viral, alcoholic or non-alcoholic hepatitis. It is a leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) representing 90% of primary liver cancer cases. Various pathways are dysregulated in HCC, including p53 and other cell cycle regulators, chromatin modifiers, oxidative stress, insulin and growth factor signalling, and Wnt/β-catenin signalling. In this issue, Senni and colleagues1 demonstrate the role of fatty acid oxidation as a source of energy in the metabolic adaptation triggered by β-catenin oncogenic activation in hepatocytes. This work describes an atypical cancer cell addiction to fatty acids and represents an important discovery that may pave the way for novel therapeutics.

The Wnt/β-catenin pathway2 plays a key role in many aspects of hepatic homeostasis, including the regulation of unique liver features, such as metabolic zonation.3 In the absence of Wnt stimulation, the cytosolic concentration of β-catenin remains low because a multiprotein complex that includes the tumour suppressor adenomatous polyposis coli (APC) promotes the phosphorylation of β-catenin, and thereby its proteasomal degradation. In response to Wnt stimulation, the degradation complex is recruited to the plasma membrane, which leads to β-catenin stabilisation, nuclear translocation and the activation of gene transcription. Altered β-catenin signalling has been found in a large proportion (11%–37%) of human HCCs.4–6 This class of tumours is due to mutations in the gene encoding β-catenin (CTNNB1) that promote its constitutive nuclear translocation and tumourigenesis due to activation of the β-catenin-dependent transcription programme. In their study, Senni et al 1 took advantage of a mouse model of HCC mimicking CTNNB1-activated human tumours through hepatocyte-specific deletion of APC.7 They used this model to characterise the impact of such oncogenic activation on cell metabolism with the aim of identifying specific metabolic pathways that could be targeted to treat such classes of HCCs.

Proliferating cells reprogramme their metabolism to meet the anabolic demand for macromolecules through various pathways. Cancer metabolism has been associated with enhanced aerobic glycolysis since Otto Warburg discovered that tumour cells convert glucose carbon to lactate, even in the presence of oxygen. This aerobic glycolytic pathway, named the Warburg effect, was considered a unique and specific example of metabolic reprogramming in cancer. Beyond glycolysis, it is now well established that other pathways are hijacked in cancer cells to promote their growth.8 In their study, Senni et al 1 show that β-catenin-activated HCCs are not glycolytic because tumours induced by APC deletion do not display altered lactate production compared with adjacent non-tumour tissue. In line with this observation, they found that β-catenin overactivation in hepatocytes does not alter their glycolytic rate, nor does it change glutaminolysis. Instead, β-catenin-activated tumours have very little triglyceride content and exhibit high ketone body levels. As ketone bodies are produced from fatty acid oxidation and reflect the fatty acid β-oxidation of hepatocytes, the authors tested the hypothesis that tumours induced by APC deletion rely on intense fatty acid catabolism as a source of energy, and thereby do not conform to the classical Warburg effect. This was further confirmed by showing that β-catenin-activated hepatocytes preferentially oxidise fatty acids and exhibit enhanced expression of critical enzymes involved in ketogenesis and elevated ketone body production (figure 1). Such increased fatty acid oxidation fuels oxidative phosphorylation and promotes the proliferation of hepatocytes lacking APC. Therefore, the rewiring of fatty acid oxidation appears to be a specific feature of β-catenin-induced oncogenic activation in hepatocytes.

Figure 1

Hepatic fatty acid catabolism is increased in β-catenin-activated hepatocellular carcinoma and can be targeted to slow the progression of the tumour.

The expression of rate-limiting enzymes involved in hepatic fatty acid oxidation and ketogenesis is under significant transcriptional control. The expression of many important proteins involved in fatty acid transport and catabolism increases during fasting. Such change in gene expression is essential for hepatic oxidation of fatty acids released from white adipose tissue and ketogenesis, which represents an alternative source of energy during hypoglycaemia. The control of this transcriptional programme involves the isotype alpha of the peroxisome proliferator-activated receptors (PPARα). PPARs are ligand-sensitive transcription factors of the nuclear hormone receptor superfamily. They act as fatty acid sensors and orchestrate almost every aspect of lipid metabolism. There are three PPAR isotypes (α, β/δ and γ), which share some structural homology but are differentially expressed among tissues and exert different biological functions. PPARα is highly expressed in hepatocytes, where it controls the expression of hundreds of genes. Hepatocyte PPARα is critical for fatty acid oxidation and required for ketogenesis. Therefore, deletion of PPARα in hepatocytes is sufficient to induce hepatic steatosis in mice.9

Senni et al 1 show that human CTNNB1-mutated HCCs have a specific pattern of gene expression related to fatty acid oxidation. They confirmed their observation using different human hepatocyte cell lines and postulated that PPARα may be involved in the dependence of β-catenin-activated HCCs on fatty acids. To challenge the notion that PPARα is involved in orchestrating the metabolic rewiring of hepatocytes with induced β-catenin activity, Senni et al deleted APC in hepatocytes of PPARα-null mice and monitored HCC progression. These mice exhibited far less tumour penetrance, as well as delayed tumour progression compared with APC-deficient mice, establishing the critical role of PPARα-dependent activity in HCC development. Moreover, Senni et al show that treatment with etomoxir, an inhibitor of carnitine palmitoyl-CoA transferase 1 (Cpt-1), a rate-limiting enzyme in fatty acid β-oxidation, is sufficient to reduce tumour growth.

Altogether, this very elegant study highlights the first example of HCCs using fatty acid oxidation as a primary energy source and provides evidence that fatty acid oxidation can be targeted to slow the progression of this tumour type. This work also reveals that enhanced fatty acid oxidation may explain why β-catenin-activated HCCs are not steatotic.10 Finally, the work of Senni and colleagues sheds light on many important and novel questions regarding the mechanistic links between β-catenin and PPARα signalling, whether β-catenin and PPARα crosstalk may directly reprogramme phospholipid metabolism, and whether such crosstalk is also involved in other β-catenin-dependent tumours.

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Footnotes

  • Contributors All authors contributed to writing and revising the commentary.

  • Competing interests None declared.

  • Patient consent Not required.

  • Provenance and peer review Commissioned; internally peer reviewed.

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