The regulation and functions of ACSL3 and ACSL4 in the liver and hepatocellular carcinoma

Abstract

Altered cellular energetics is one of the hallmarks of cancer 1,2 and intratumoural lipid metabolism tends to be markedly changed in hepatocellular carcinoma (HCC) 1,[3][4][5] where it manifests as altered intracellular levels triacylglycerol (TAG), phospholipids, cholesterol and ceramide. 3,[6][7][8][9][10][11][12][13][14][15][16][17][18][19] HCC is one of the world's most common cancers 20,21 and can develop from chronic liver diseases that feature dysregulated lipid metabolism, inflammation and hepatocellular death. This pathological sequence is illustrated well in the case of non-alcoholic fatty liver disease (NAFLD) which can lead to nonalcoholic steatohepatitis (NASH) 21,22 and ultimately NASH-HCC. 23 Rewired lipid metabolism in HCC can also be characteristic of different oncogene driver mutations. For example, hepatomas with a CNNTB1 mutation encoding β-catenin are generally 'addicted' to mitochondrial fatty acid β-oxidation (FAO) 24 and have low levels of

Crosstalk between Epigenetics and Metabolic Reprogramming in Metabolic Dysfunction-Associated Steatotic Liver Disease-Induced Hepatocellular Carcinoma: A New Sight

“…Deletion of FOXK1 improves the progression from MASLD to MASH and, eventually, HCC by boosting the breakdown of lipids within liver cells [ 115 ]. ACSL3, a member of the long-chain acyl-CoA synthetase family, and ACSL4 play crucial roles in FA activation and are commonly upregulated in HCC [ 116 ]. In MASH, the overexpression of ACSL4 leads to enhanced steatosis by inhibiting FAO [ 117 ], whereas elevated ACSL4 levels in hepatomas contribute to heightened lipogenesis by indirectly boosting SREBP1 activity [ 118 ].…”

Review article: Hepatic steatosis and its associations with acute and chronic liver diseases

“…LDs as they form 135 and may have an important role in supplying fatty acids for triglyceride synthesis while the nascent LD is associated with the ER. 136 In yeast, the ER-LD interface is the site of inhibition of the ceramide-producing enzymes serine palmitoyltransferase and fatty acid elongase by the seipin orthologue, and expression of human seipin rescues sphingolipid production inhibitor-induced growth phenotypes in seipin knockout yeast. 137 Seipin proteins are targeted by polyunsaturated fatty acids and cyclopropane fatty acids to ER subdomains involved in LD development, 138 where the seipin oligomer forms cage-like structures.…”

“…Many cellular LDs associate with the ER membrane in vivo, 134 and the ER–LD interface is important for regulation of lipid metabolism. Long‐chain acyl‐coenzyme A synthetase 3 (ASCL3) distributes to LDs as they form 135 and may have an important role in supplying fatty acids for triglyceride synthesis while the nascent LD is associated with the ER 136 . In yeast, the ER‐LD interface is the site of inhibition of the ceramide‐producing enzymes serine palmitoyltransferase and fatty acid elongase by the seipin orthologue, and expression of human seipin rescues sphingolipid production inhibitor‐induced growth phenotypes in seipin knockout yeast 137 .…”