Fatty acid metabolism reprogramming in ccRCC: mechanisms and potential targets

Abstract

Lipid droplet formation is a defining histological feature in clear-cell renal cell carcinoma (ccRCC) but the underlying mechanisms and importance of this biological behaviour have remained enigmatic. De novo fatty acid (FA) synthesis, uptake and suppression of FA oxidation have all been shown to contribute to lipid storage, which is a necessary tumour adaptation rather than a bystander effect. Clinical studies and mechanistic investigations into the roles of different enzymes in FA metabolism pathways have revealed new metabolic vulnerabilities that hold promise for clinical effect. Several metabolic alterations are associated with worse clinical outcomes in patients with ccRCC, as lipogenic genes drive tumorigenesis. Enzymes involved in the intrinsic FA metabolism pathway include FA synthase, acetyl-CoA carboxylase, ATP citrate lyase, stearoyl-CoA desaturase 1, cluster of differentiation 36, carnitine palmitoyltransferase 1A and the perilipin family, and each might be potential therapeutic targets in ccRCC owing to the link between lipid deposition and ccRCC risk. Adipokines and lipid species are potential biomarkers for diagnosis and treatment monitoring in patients with ccRCC. FA metabolism could potentially be targeted for therapeutic intervention in ccRCC as small-molecule inhibitors targeting the pathway have shown promising results in preclinical models.

Fig. 1 |. H&E staining of ccrCC and normal adjacent kidney tissues.

a | The ‘clear’ cytoplasm seen in clear-cell renal cell carcinoma (ccRCC) tissue sections compared with b | non-malignant adjacent tissue shows the washout of lipid and glycogen content during histological preparation, which also gives the name to this disease.

Fig. 2 |. VHl and HIF pathway regulation in ccrCC.

In clear-cell renal cell carcinoma (ccRCC), von Hippel–Lindau (VHL) inactivation leads to hypoxia-inducible factor (HIF)1α and HIF2α stabilization irrespective of oxygenation status (although HIF1α protein lost in roughly 30% of ccRCC, and HIF2α has been argued to be the driving oncogenic subunit^–). Stabilized HIFα translocates to the nucleus, dimerizes with HIFβ and functions as a transcription factor through binding to conserved hypoxia response elements (HREs) present in hypoxia-responsive genes, such as SLC2A1, PDK1, HK2 and LDHA, HIFα translocation and dimerization with HIFβ also results in repression of CPT1A transcription. VHL inactivation also results in stabilization of PPARγ, which translocases to nucleus to bind to PPRE, activating transcription of lipogenic gene ACLY. CPT1A, carnitine palmitoyltransferase 1A; SLC2A1, glucose transporter 1; HK2, hexokinase 2; LDHA, lactate dehydrogenase A; PDK1, pyruvate dehydrogenase kinase 1; PPARγ, peroxisome proliferator-activated receptor-γ; PPRE, PPAR response elements.

Fig. 3 |. Fatty acid metabolism pathways in clear-cell renal cell carcinoma and potential therapeutic targets.

Fatty acids (FAs) are the products of de novo lipogenesis, are carboxylic acid molecules with an unbranched aliphatic chain, and can be either saturated or unsaturated. In de novo lipogenesis, cells synthesize citrate from glucose, acetate and glutamine. Palmitate (16:0 FA) is produced via a multistep process: through the action of ATP-citrate lyase (ACLY), citrate is cleaved into oxaloacetate and acetyl-coenzyme A (acetyl-CoA). In the cytosol, acetyl-CoA is irreversibly carboxylated to form malonyl-CoA via acetyl-CoA carboxylase (ACC), which is the rate-limiting step. FA synthase (FASN) later elongates the malonyl-CoA into long-chain FAs. Palmitate can then be further elongated by FA elongases (such as ELOVL6) or desaturated by stearoyl-CoA desaturase (SCD). Exogeneous FAs can be transported into cells by CD36 located on the plasma membrane. Both exogenously and endogenously sourced FAs can be stored as triacylglycerol (TAG) in lipid droplets. FAs can alternatively be transported into mitochondria via carnitine palmitoyltransferase 1 A (CPT1A) for mitochondrial β-oxidation, providing an energy source through the production of ATP. The highly relevant targets that are described in this Review are highlighted in green. ACC, acetyl-CoA carboxylase; ACLY, ATP-citrate lyase; ACSL, long-chain acyl-CoA synthetase; ACSS2, acyl Co-A synthethase-2; Asp, aspartate; FASN, FA synthase; FATP2, fatty acid transport protein 2; Fum, fumarate; GLS, glutaminase; GLUT1, glucose transporter 1; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; Mal, malate; MCT, monocarboxylate transporter; MUFA, monounsaturated FA; Oac, oxaloacetate; PA, phosphatidic acid; PL, phospholipid; PUFA, polyunsaturated FA; SFA, saturated FA; TCA, tricyclic acid cycle.