Plasma lipidomics identifies a signature of NAFLD in children that couples with cardiometabolic outcomes in adults

Mann, Jake; Furse, Samuel; Snowden, Stuart G.; Alisi, Anna; Draijer, Laura G.; investigators, Eu-Pnafld; Jenkins, Benjamin; Karnebeek, Kylie; Kelly, Déirdre; Koot, Bart; Mosca, Antonella; Salvestrini, Camilla; Mourik, Indra van; Vreugdenhil, Anita; Koulman, Albert

doi:10.1101/2020.04.18.20070417

Cited by 3 publications

(2 citation statements)

References 67 publications

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“…Plasma lipidomics was performed in a subset of 129 children with NAFLD who had undergone liver biopsy. The methods have been described in detail elsewhere 49 , but in brief, lipids, triglycerides and sterols were extracted together from fasting plasma using a high throughput technique followed by direct infusion mass spectrometry (DI-MS) 50 .…”

Section: Methodsmentioning

confidence: 99%

Variants in MARC1 and HSD17B13 reduce severity of NAFLD in children, perturb phospholipid metabolism, and suppress fibrotic pathways

Hudert

Alisi

Anstee

et al. 2020

Preprint

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Background & aims: Genome-wide association studies in adults have identified variants in HSD17B13 and MARC1 as protective against NAFLD. It is not known if they are similarly protective in children and, more generally, whether the peri-portal inflammation of pediatric NAFLD and lobular inflammation seen in adults share common genetic influences. Therefore, we aimed to: establish if these variants are associated with NAFLD in children, and to investigate the function of these variants in hepatic metabolism using metabolomics. Methods: 960 children (590 with NAFLD, 394 with liver histology) were genotyped for rs72613567T>TA in HSD17B13, rs2642438G>A in MARC1. Genotype-histology associations were tested using ordinal regression. Untargeted hepatic proteomics and plasma lipidomics were performed in a subset of samples. In silico tools were used to model the effect of rs2642438G>A (p.Ala165Thr) on MARC1. Results: rs72613567T>TA in HSD17B13 was associated with lower odds of NAFLD diagnosis (OR 0.7 (95%CI 0.6-0.9) and lower grade of portal inflammation (P<0.001) whilst rs2642438G>A in MARC1 was associated with lower grade of hepatic steatosis (P=0.02). Proteomics found reduced expression of HSD17B13 in carriers of the protective allele, whereas MARC1 levels were not affected by genotype. Both variants showed downregulation of hepatic fibrotic pathways, upregulation of retinol metabolism and perturbation of phospholipid species. Modelling suggests that p.Ala165Thr would disrupt the stability and metal-binding of MARC1. Conclusions: There are shared genetic mechanisms between pediatric and adult NAFLD, despite their differences in histology. MARC1 and HSD17B13 are involved in phospholipid metabolism and suppress fibrosis in NAFLD.

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Section: Methodsmentioning

confidence: 99%

Variants in MARC1 and HSD17B13 reduce severity of NAFLD in children, perturb phospholipid metabolism, and suppress fibrotic pathways

Hudert

Alisi

Anstee

et al. 2020

Preprint

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“…However, TM6SF2 knockdown significantly increased in lysoPC and lysoPE, both of which were recently identified as early biomarkers of NAFLD and are increased in NALFD patients with hepatitis [22]. LysoPC has also been previously shown to be increased in liver of NASH patients [23][24][25]. However, lysoPE, but not lysoPCs, were also increased by wild-type overexpression; therefore, further study is needed to determine the significance of these changes.…”

Section: Discussionmentioning

confidence: 96%

Perturbation of TM6SF2 Expression Alters Lipid Metabolism in a Human Liver Cell Line

Pant

Chen

Kuppa

et al. 2021

IJMS

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Non-alcoholic fatty liver disease (NAFLD) is caused by excess lipid accumulation in hepatocytes. Genome-wide association studies have identified a strong association of NAFLD with non-synonymous E167K amino acid mutation in the transmembrane 6 superfamily member 2 (TM6SF2) protein. The E167K mutation reduces TM6SF2 stability, and its carriers display increased hepatic lipids and lower serum triglycerides. However, the effects of TM6SF2 on hepatic lipid metabolism are not completely understood. We overexpressed wild-type or E167K variant of TM6SF2 or knocked down TM6SF2 expression in lipid-treated Huh-7 cells and used untargeted lipidomic analysis, RNAseq transcriptome analysis, and fluorescent imaging to determine changes in hepatic lipid metabolism. Both TM6SF2 knockdown and E167K overexpression increased hepatic lipid accumulation, while wild-type overexpression decreased acylglyceride levels. We also observed lipid chain remodeling for acylglycerides by TM6SF2 knockdown, leading to a relative increase in species with shorter, more saturated side chains. RNA-sequencing revealed differential expression of several lipid metabolizing genes, including genes belonging to AKR1 family and lipases, primarily in cells with TM6SF2 knockdown. Taken together, our data show that overexpression of TM6SF2 gene or its loss-of-function changes hepatic lipid species composition and expression of lipid metabolizing genes. Additionally, our data further confirms a loss-of-function effect for the E167K variant.

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Variants in mitochondrial amidoxime reducing component 1 and hydroxysteroid 17‐beta dehydrogenase 13 reduce severity of nonalcoholic fatty liver disease in children and suppress fibrotic pathways through distinct mechanisms

et al. 2022

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Genome‐wide association studies in adults have identified variants in hydroxysteroid 17‐beta dehydrogenase 13 (HSD17B13) and mitochondrial amidoxime reducing component 1 (MTARC1) as protective against nonalcoholic fatty liver disease (NAFLD). We aimed to test their association with pediatric NAFLD liver histology and investigate their function using metabolomics. A total of 1450 children (729 with NAFLD, 399 with liver histology) were genotyped for rs72613567T>TA in HSD17B13, rs2642438G>A in MTARC1, and rs738409C>G in patatin‐like phospholipase domain‐containing protein 3 (PNPLA3). Genotype–histology associations were tested using ordinal regression. Untargeted hepatic proteomics and plasma lipidomics were performed in a subset of children. We found rs72613567T>TA in HSD17B13 to be associated with lower odds of NAFLD diagnosis (odds ratio, 0.7; 95% confidence interval, 0.6–0.9) and a lower grade of portal inflammation (p < 0.001). rs2642438G>A in MTARC1 was associated with a lower grade of hepatic steatosis (p = 0.02). Proteomics found reduced expression of HSD17B13 in carriers of the protective ‐TA allele. MTARC1 levels were unaffected by genotype. Both variants were associated with down‐regulation of fibrogenic pathways. HSD17B13 perturbs plasma phosphatidylcholines and triglycerides. In silico modeling suggested p.Ala165Thr disrupts the stability and metal binding of MTARC1. Conclusion: Both HSD17B13 and MTARC1 variants are associated with less severe pediatric NAFLD. These results provide further evidence for shared genetic mechanisms between pediatric and adult NAFLD.

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Plasma lipidomics identifies a signature of NAFLD in children that couples with cardiometabolic outcomes in adults

Cited by 3 publications

References 67 publications

Variants in MARC1 and HSD17B13 reduce severity of NAFLD in children, perturb phospholipid metabolism, and suppress fibrotic pathways

Variants in MARC1 and HSD17B13 reduce severity of NAFLD in children, perturb phospholipid metabolism, and suppress fibrotic pathways

Perturbation of TM6SF2 Expression Alters Lipid Metabolism in a Human Liver Cell Line

Variants in mitochondrial amidoxime reducing component 1 and hydroxysteroid 17‐beta dehydrogenase 13 reduce severity of nonalcoholic fatty liver disease in children and suppress fibrotic pathways through distinct mechanisms

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