Lipid Metabolism in Development and Progression of Hepatocellular Carcinoma

Abstract

: 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.

Keywords: fatty acid β-oxidation; hepatocellular carcinoma; lipid metabolism; lipidomics; non-alcoholic fatty liver disease; tumour progression.

Figure 1

Enhancement of fatty acid synthesis in hepatocellular carcinoma (HCC). ATP citrate lyase (ACLY); acetyl-CoA carboxylase (ACC); fatty acid synthase (FASN); stearoyl-CoA desaturase (SCD); fatty acid (FA); monounsaturated fatty acid (MUFA); tricarboxylic acid cycle (TCA cycle); sterol regulatory element-binding protein1 (SREBP1c); peroxisome proliferator-activated receptor-γ coactivator beta (PGC-1β).

Figure 2

Different conditions influencing β-oxidation in HCC and proposed mechanisms. In a “lipid-rich condition” (e.g., obesity, non-alcoholic steato-hepatitis (NASH)) carnitine palmitoyltransferase 1A (CPT1A) is up-regulated, while CPT2 is down-regulated with consequent accumulation of pro-carcinogenic acylcarnitine and lower availability of acyl-CoA to sustain β-oxidation. Hypoxia has also been associated with β-oxidation suppression, as hypoxia inducible factor 1-α (HIF-1α) is induced and inhibits the expression of medium- and long-chain acyl-CoA dehydrogenases (MCAD and LCAD), two rate-limiting enzymes involved in the first β-oxidation steps. In contrast, in βcatenin-activated HCC, β-oxidation is fuelled by CPT2 activity, while peroxisome proliferator activated receptor alpha (PPARα) is up-regulated and induces the expression of LCAD and MCAD. During nutrient deficiency, 5′ adenosine monophosphate-activated protein kinase (AMPK) phosphorylates ACCα, permits CPT1A migration to the mitochondrial membrane to transport FAs and sustain β-oxidation. Fatty acid (FA); carnitine palmitoyltransferase 1A (CPT1A); carnitine palmitoyltransferase 2 (CPT2); medium-chain acyl-CoA dehydrogenases (MCAD); long-chain acyl-CoA dehydrogenases (LCAD); hypoxia inducible factor 1-α (HIF-1α); peroxisome proliferator activated receptor alpha (PPARα); 5′ adenosine monophosphate-activated protein kinase (AMPK); acetyl-CoA carboxylase alpha (ACCα).