Fatty acid metabolism and acyl-CoA synthetases in the liver-gut axis

Fatty acids are energy substrates and cell components which participate in regulating signal transduction,transcription factor activity and secretion of bioactive lipid mediators.The acyl-CoA synthetases(ACSs)family containing 26 family members exhibits tissue-specific distribution,distinct fatty acid substrate preferences and diverse biological functions.Increasing evidence indicates that dysregulation of fatty acid metabolism in the liver-gut axis,designated as the bidirectional relationship between the gut,microbiome and liver,is closely associated with a range of human diseases including metabolic disorders,inflammatory disease and carcinoma in the gastrointestinal tract and liver.In this review,we depict the role of ACSs in fatty acid metabolism,possible molecular mechanisms through which they exert functions,and their involvement in hepatocellular and colorectal carcinoma,with particular attention paid to long-chain fatty acids and small-chain fatty acids.Additionally,the liver-gut communication and the liver and gut intersection with the microbiome as well as diseases related to microbiota imbalance in the liver-gut axis are addressed.Moreover,the development of potentially therapeutic small molecules,proteins and compounds targeting ACSs in cancer treatment is summarized.

Metformin alleviates spinal cord injury by inhibiting nerve cell ferroptosis through upregulation of heme oxygenase-1 expression

Previous studies have reported upregulation of heme oxygenase-1 in different central nervous system injury models.Heme oxygenase-1 plays a critical anti-inflammatory role and is essential for regulating cellular redox homeostasis.Metformin is a classic drug used to treat type 2 diabetes that can inhibit ferroptosis.Previous studies have shown that,when used to treat cardiovascular and digestive system diseases,metformin can also upregulate heme oxygenase-1 expression.Therefore,we hypothesized that heme oxygenase-1 plays a significant role in mediating the beneficial effects of metformin on neuronal ferroptosis after spinal cord injury.To test this,we first performed a bioinformatics analysis based on the GEO database and found that heme oxygenase-1 was upregulated in the lesion of rats with spinal cord injury.Next,we confirmed this finding in a rat model of T9 spinal cord compression injury that exhibited spinal cord nerve cell ferroptosis.Continuous intraperitoneal injection of metformin for 14 days was found to both upregulate heme oxygenase-1 expression and reduce neuronal ferroptosis in rats with spinal cord injury.Subsequently,we used a lentivirus vector to knock down heme oxygenase-1 expression in the spinal cord,and found that this significantly reduced the effect of metformin on ferroptosis after spinal cord injury.Taken together,these findings suggest that metformin inhibits neuronal ferroptosis after spinal cord injury,and that this effect is partially dependent on upregulation of heme oxygenase-1.

ACSL5,a prognostic factor in acute myeloid leukemia,modulates the activity of Wnt/β-catenin signaling by palmitoylation modification

Acyl-CoA synthetase long chain family member 5(ACSL5),is a member of the acyl-CoA synthetases(ACSs)family that activates long chain fatty acids by catalyzing the synthesis of fatty acyl-CoAs.The dysregulation of ACSL5 has been reported in some cancers,such as glioma and colon cancers.However,little is known about the role of ACSL5 in acute myeloid leukemia(AML).We found that the expression of ACSL5 was higher in bone marrow cells from AML patients compared with that from healthy donors.ACSL5 level could serve as an independent prognostic predictor of the overall survival of AML patients.In AML cells,the ACSL5 knockdown inhibited cell growth both in vitro and in vivo.Mechanistically,the knockdown of ACSL5 suppressed the activation of the Wnt/β-catenin pathway by suppressing the palmitoylation modification of Wnt3a.Additionally,triacsin c,a pan-ACS family inhibitor,inhibited cell growth and robustly induced cell apoptosis when combined with ABT-199,the FDA approved BCL-2 inhibitor for AML therapy.Our results indicate that ACSL5 is a potential prognosis marker for AML and a promising pharmacological target for the treatment of molecularly stratified AML.