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Exploiting three-dimensional human hepatic constructs to investigate the impact of rs174537 on fatty acid metabolism.

ABSTRACT: The Modern Western Diet has been associated with the rise in metabolic and inflammatory diseases, including obesity, diabetes, and cardiovascular disease. This has been attributed, in part, to the increase in dietary omega-6 polyunsaturated fatty acid (PUFA) consumption, specifically linoleic acid (LA), arachidonic acid (ARA), and their subsequent metabolism to pro-inflammatory metabolites which may be driving human disease. Conversion of dietary LA to ARA is regulated by genetic variants near and within the fatty acid desaturase (FADS) haplotype block, most notably single nucleotide polymorphism rs174537 is strongly associated with FADS1 activity and expression. This variant and others within high linkage disequilibrium may potentially explain the diversity in both diet and inflammatory mediators that drive chronic inflammatory disease in human populations. Mechanistic exploration into this phenomenon using human hepatocytes is limited by current two-dimensional culture models that poorly replicate in vivo functionality. Therefore, we aimed to develop and characterize a three-dimensional hepatic construct for the study of human PUFA metabolism. Primary human hepatocytes cultured in 3D hydrogels were characterized for their capacity to represent basic lipid processing functions, including lipid esterification, de novo lipogenesis, and cholesterol efflux. They were then exposed to control and LA-enriched media and reproducibly displayed allele-specific metabolic activity of FADS1, based on genotype at rs174537. Hepatocytes derived from individuals homozygous with the minor allele at rs174537 (i.e., TT) displayed the slowest metabolic conversion of LA to ARA and significantly reduced FADS1 and FADS2 expression. These results support the feasibility of using 3D human hepatic cultures for the study of human PUFA and lipid metabolism and relevant gene-diet interactions, thereby enabling future nutrition targets in humans.

SUBMITTER: Kirk LM

PROVIDER: S-EPMC8775235 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHuman and animal studies have raised concerns that supplemental selenium can increase the risk of metabolic disorders, but underlying mechanisms are unclear.ObjectiveWe used an integrated transcriptome and metabolome analysis of liver to test for functional pathway and network responses to supplemental selenium in mice.MethodsMale mice (8-wk-old, C57BL/6J) fed a standard diet (0.41 ppm Se) were given selenium (Na2SeO4, 20 μmol/L) or vehicle (drinking water) for 16 wk. Livers were analyzed for selenium concentration, activity of selenoproteins, reduced glutathione (GSH) redox state, gene expression, and high-resolution metabolomics. Transcriptomic and nontargeted metabolomic data were analyzed with biostatistics, bioinformatics, pathway enrichment analysis, and combined transcriptome-metabolome-wide association study (TMWAS).ResultsMice supplemented with selenium had greater body mass gain from baseline to 16 wk (55% ± 5%) compared with controls (40% ± 3%) (P < 0.05); however, no difference was observed in liver selenium content, selenoenzyme transcripts, or enzyme activity. Selenium was higher in the heart, kidney, and urine of mice supplemented with selenium. Gene enrichment analysis showed that supplemental selenium altered pathways of lipid and energy metabolism. Integrated transcriptome and metabolome network analysis showed 2 major gene-metabolite clusters, 1 centered on the transcript for the bidirectional glucose transporter 2 (Glut2) and the other centered on the transcripts for carnitine-palmitoyl transferase 2 (Cpt2) and acetyl-CoA acyltransferase (Acaa1). Pathway analysis showed that highly associated metabolites (P < 0.05) were enriched in fatty acid metabolism and bile acid biosynthesis, including acylcarnitines, triglycerides and glycerophospholipids, long-chain acyl-coenzyme As, phosphatidylcholines, and sterols. TMWAS of body weight gain confirmed changes in the same pathways.ConclusionsSupplemental selenium in mice alters hepatic fatty acid and energy metabolism and causes increases in body mass. A lack of effect on hepatic selenium content suggests that signaling involves an extrahepatic mechanism.

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Exploiting three-dimensional human hepatic constructs to investigate the impact of rs174537 on fatty acid metabolism.

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