Squalene through Its Post-Squalene Metabolites Is a Modulator of Hepatic Transcriptome in Rabbits

Abstract

Squalene is a natural bioactive triterpene and an important intermediate in the biosynthesis of sterols. To assess the effect of this compound on the hepatic transcriptome, RNA-sequencing was carried out in two groups of male New Zealand rabbits fed either a diet enriched with 1% sunflower oil or the same diet with 0.5% squalene for 4 weeks. Hepatic lipids, lipid droplet area, squalene, and sterols were also monitored. The Squalene administration downregulated 9 transcripts and upregulated 13 transcripts. The gene ontology of transcripts fitted into the following main categories: transporter of proteins and sterols, lipid metabolism, lipogenesis, anti-inflammatory and anti-cancer properties. When the results were confirmed by RT-qPCR, rabbits receiving squalene displayed significant hepatic expression changes of LOC100344884 (PNPLA3), GCK, TFCP2L1, ASCL1, ACSS2, OST4, FAM91A1, MYH6, LRRC39, LOC108176846, GLT1D1 and TREH. A squalene-enriched diet increased hepatic levels of squalene, lanosterol, dihydrolanosterol, lathosterol, zymostenol and desmosterol. Strong correlations were found among specific sterols and some squalene-changed transcripts. Incubation of the murine AML12 hepatic cell line in the presence of lanosterol, dihydrolanosterol, zymostenol and desmosterol reproduced the observed changes in the expressions of Acss2, Fam91a1 and Pnpla3. In conclusion, these findings indicate that the squalene and post-squalene metabolites play important roles in hepatic transcriptional changes required to protect the liver against malfunction.

Differentially Expressed Genes in Response to a Squalene-Supplemented Diet Are Accurate Discriminants of Porcine Non-Alcoholic Steatohepatitis

“…In the porcine model used in this study, the administration of the diet over a short period promoted NASH with an identical distribution of cellular ballooning grades 1 and 2, as determined by the steatosis activity fibrosis (SAF) score and FLIP algorithm [ 32 ]. The amount of squalene chosen was similar to that administered to rabbits, which induced changes in the hepatic transcriptome [ 30 ]. This amount would also represent an adapted metabolic rate of the 1% squalene-containing diets used in mice [ 29 , 40 ].…”

“…In cultured human hepatocytes, squalene modified the expression of lipid metabolism genes, leading to crucially lower triacylglycerols and cholesterol content, when cellular uptake of fatty acids was increased [ 43 ]. In other models, squalene has been found to influence a cluster of genes related to lipid content [ 29 , 30 ]. The difference in responses could be related to species-specific expression patterns or to experimental settings.…”

“…Previous studies showed that squalene exerts anti-neoplastic effects [ 30 , 71 ]. PPP1R1B is activated in colorectal liver metastasis [ 72 ].…”

“…The accumulation of squalene in the liver of mice was associated with complex transcriptional and post-translational changes in gene expressions, including of Mat1 , Acox1 , Casp1 , Cyp2b10 , Cyp2c55 , Cpt1a , and Txndc5 [ 27 , 28 , 29 ]. In contrast, the hepatic changes in rabbit involved PNPLA3 , GCK , TFCP2L1 , ASCL1 , ACSS2 , OST4 , FAM91A1 , MYH6 , LRRC39 , LOC108176846 , GLT1D1 , and TREH [ 30 ]. These discrepant findings in animal models need further confirmation in different models and might indicate varied metabolic responses in humans.…”

A Comprehensive Review of Health-Benefiting Components in Rapeseed Oil

“…Squalene, a biofunctional lipid compound, is reported to have diverse bioactivities ranging from cardioprotective, antioxidant, chemopreventive, anti-cancerous, anti-lipidemic, and membrane-stabilizing properties, among others [ 68 ]. A previous study showed that squalene could enhance serum high-density lipoprotein cholesterol levels and reduce oxidative stress [ 69 ]. It has been revealed that squalene and post-squalene metabolites are modulators of hepatic transcriptional changes in rabbits, thus protecting the liver against dysfunction [ 70 ].…”