In proliferative cells, de novo lipogenesis is induced by overexpressing the genes involved in FA synthesis (IMAGE)

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In proliferative cells, de novo lipogenesis is induced by overexpressing the genes involved in FA synthesis

Caption

These include ACLY, ACC, and FASN, regulated by transcription factor SREBP1c. In HCC, SREBP1c can be overexpressed by P13K/Akt/mTOR pathway activated by CD147 and its downstream molecules, such as FOXO1, GSK3, and LPIN1. Hyperlipidemia triggers the release of FGL1, which is a suppressor of the Akt/mTOR pathway. On the other hand, beta-oxidation can be suppressed by inhibiting the p38/MAPKs/PPARα/CPT1A/ACOX1 pathway mediated by CD147. In regenerative cells, HNF-1α and phosphorylated STAT3 can upregulate FGL1, triggering proliferative pathways like EGFR/Src/ERK. Nonetheless, in HCC, deletion of HNF-1α downregulates FGL1 promoter, which in turn reduces the secretion of SREBP. Under hypoxic conditions, the JAK2/STAT3 pathway induces HIF-1α, which inhibits beta-oxidation by inhibiting mitochondrial enzymes like MCAD and LCAD. ACC, acetyl-CoA carboxylase; ACOX1, acyl-CoA oxidase 1; AKT, Ak strain transforming; ACL, ATP-citrate lyase; CPT1A, carnitine palmitoyltransferase I; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FASN, fatty acid synthase; FGL1, fibrinogen-like protein 1; FOXO1, forkhead box protein O1; GP130, glycoprotein 130; GSK3, glycogen-synthase kinase-3; HIF-1α, hypoxia-inducible factor-1 alpha; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; HNF-1α, hepatocyte nuclear factor-1 alpha; IL6-R, interleukin-6 receptor; JAK2, Janus kinase 2; LDLR, low-density lipoprotein receptor; LCAD, long-chain acyl-CoA dehydrogenase; MAPKs, mitogen-activated protein kinases; MCAD, medium-chain acyl-CoA dehydrogenase; MEK, mitogen-activated ERK kinase; MUFAs, monounsaturated fatty acids; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol-3-kinase; PPARα, peroxisome proliferator-activated receptor alpha; RAS, rat sarcoma; SCD, stearoyl-CoA desaturase; SREBP1c, sterol regulatory element-binding protein 1c; STAT3, signal transducer and activator of transcription 3.

Credit

Xiaolei Miao, Zahra Shafieizadeh, Zohreh Shafieizadeh

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