Plasma 3-hydroxyisobutyrate (3-HIB) and methylmalonic acid (MMA) are markers of hepatic mitochondrial fatty acid oxidation in male Wistar rats

Bjune, Mona S; Lindquist, Carine; Stafsnes, Marit Hallvardsdotter; Bjørndal, Bodil; Bruheim, Per; Aloysius, Thomas A.; Nygård, Ottar; Skorve, Jon; Madsen, Lise; Dankel, Simon N.; Berge, Rolf K.

doi:10.1016/j.bbalip.2021.158887

Cited by 14 publications

(12 citation statements)

References 56 publications

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“…HCY could induce steatosis by increasing de novo lipogenesis through the upregulation of ER stress [ 37 ]. In Wistar rats, MMA was elevated in diet-induced hepatic steatosis and was identified as a novel circulating marker reflecting mitochondrial β-oxidation [ 38 ]. A recent study found that MMA accumulation induced by MMUT deficiency was involved in metabolic and mitochondrial alterations that were exacerbated by anomalies in PINK1/Parkin-mediated mitophagy, causing the accumulation of dysfunctional mitochondria and triggering epithelial stress and ultimately cell damage [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

The Association between Non-Alcoholic Fatty Liver Disease (NAFLD) and Advanced Fibrosis with Serological Vitamin B12 Markers: Results from the NHANES 1999–2004

Huang

Yang

et al. 2022

Nutrients

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Background: There is evidence that vitamin B12 and associated metabolite levels are changed in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH); however, their association has been in dispute. Methods: We included 8397 individuals without previous liver condition or excess alcohol intake from the National Health and Nutrition Examination Survey (NHANES) 1999–2004. NAFLD was diagnosed with Fatty Liver Index (FLI) ≥ 60 or USFLI ≥ 30, and participants with advanced fibrosis risks were identified with elevated non-alcoholic fatty liver disease fibrosis score (NFS), fibrosis 4 index (FIB-4), or aspartate aminotransferase (AST)/platelet ratio index (APRI). Step-wide logistic regression adjusting for confounders was used to detect the association between NAFLD or advanced fibrosis with serum vitamin B12, folate, red blood cell folate (RBC folate), homocysteine (HCY), and methylmalonic acid (MMA). Results: The weighted prevalence of NAFLD was 44.2%. Compared with non-NAFLD participants, patients with NAFLD showed significantly increased RBC folate level and RBC counts, decreased serum vitamin B12 and folate, and similar HCY and MMA levels. NAFLD with advanced fibrosis risk had higher MMA and HCY, reduced serum vitamin B12, and similar serum folate and RBC folate levels than NAFLD with low fibrosis risk. Only RBC folate was independently associated with an increased risk of NAFLD (OR (95% CI): 2.24 (1.58, 3.18)). In all participants, MMA (OR: 1.41 (1.10, 1.80)) and HCY (OR: 2.76 (1.49, 5.11)) were independently associated with increased risk for advanced fibrosis. In participants with NAFLD, this independent association still existed (OR: 1.39 (1.04, 1.85) for MMA and 1.95 (1.09, 3.46) for HCY). In all patients, the area under the receiver operating characteristic curve (ROC AUC) on fibrosis was 0.6829 (0.6828, 0.6831) for MMA and 0.7319 (0.7318, 0.7320) for HCY; in participants with NAFLD, the corresponding ROC AUC was 0.6819 (0.6817, 0.6821) for MMA and 0.6926 (0.6925, 0.6928) for HCY. Conclusion: Among vitamin B12-associated biomarkers, RBC folate was independently associated with elevated NAFLD risk, whereas MMA and HCY were associated with increased risk for advanced fibrosis in the total population and NAFLD participants. Our study highlighted the clinical diagnostic value of vitamin B12 metabolites and the possibility that vitamin B12 metabolism could be a therapeutic target for NASH. Further studies using recent perspective data with biopsy proven NASH could be conducted to validate our results.

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Section: Discussionmentioning

confidence: 99%

The Association between Non-Alcoholic Fatty Liver Disease (NAFLD) and Advanced Fibrosis with Serological Vitamin B12 Markers: Results from the NHANES 1999–2004

Huang

Yang

et al. 2022

Nutrients

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“…Abnormal accumulation of MMA disrupts normal glucose and glutamic acid metabolism in the rat liver ( Toyoshima et al, 1996 ). Another study proposed MMA as a biomarker reflecting the degree of hepatic mitochondrial fatty acid oxidation in rats ( Bjune et al, 2021 ). AEPE treatment significantly decreased the MMA content in the feces of NAFLD mice.…”

Section: Discussionmentioning

confidence: 99%

Phyllanthus emblica aqueous extract retards hepatic steatosis and fibrosis in NAFLD mice in association with the reshaping of intestinal microecology

et al. 2022

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Accumulating evidence suggests that dysregulation of the intestinal flora potentially contributes to the occurrence and development of nonalcoholic fatty liver disease (NAFLD). Phyllanthus emblica (PE), an edible and medicinal natural resource, exerts excellent effects on ameliorating NAFLD, but the potential mechanism remains unclear. In the present study, a mouse NAFLD model was established by administering a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). The protective effects of the aqueous extract of PE (AEPE) on the gut microbiota and fecal metabolites in NAFLD mice were detected by performing 16S rRNA gene sequencing and untargeted metabolomics. The administration of middle- and high-dose AEPE decreased the levels of ALT, AST, LDL-C, TG, and Hyp and increased HDL-C levels in CDAHFD-fed mice. Hematoxylin–eosin (H&E), Oil Red O, and Masson’s trichrome staining indicated that AEPE treatment attenuated hepatic steatosis and fibrotic lesions. Moreover, the disordered intestinal microflora was remodeled by AEPE, including decreases in the abundance of Peptostreptococcaceae, Faecalibaculum, and Romboutsia. The untargeted metabolomics analysis showed that AEPE restored the disturbed glutathione metabolism, tryptophan metabolism, taurine and hypotaurine metabolism, and primary bile acid biosynthesis of the gut bacterial community in NAFLD mice, which strongly correlated with hepatic steatosis and fibrosis. Collectively, AEPE potentially ameliorates NAFLD induced by a CDAHFD through a mechanism associated with its modulatory effects on the gut microbiota and microbial metabolism.

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“…The metabolite 3-hydroxyisobutyric acid is transformed further to succinyl coenzyme A which is involved in the metabolism of the tricarboxylic acid (TCA) cycle. A prior research has reported the involvement of HIBCH in hepatic mitochondrial fatty acid oxidation [30]. Various studies have shown that HIBCH is related to colorectal cancer [31], ovarian cancer [32,33], prostate cancer [34], paroxysmal dyskinesia [35], and Leigh syndrome [36][37][38][39].…”

Section: Discussionmentioning

confidence: 99%

Identification of HIBCH as a Fatty Acid Metabolism-Related Biomarker in Aortic Valve Calcification Using Bioinformatics

Chen

Sun

Xiong

et al. 2022

Oxidative Medicine and Cellular Longevity

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Objective. To identify fatty acid metabolism-related biomarkers of aortic valve calcification (AVC) using bioinformatics and to research the role of immune cell infiltration for AVC. Methods. The AVC dataset was retrieved from the Gene Expression Omnibus database. R package is used for differential expression genes analysis and weighted gene coexpression analysis. The differentially coexpressed genes were identified by the Venn diagram, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of differentially coexpressed genes. Functions closely related to AVC were identified by GO and KEGG enrichment analyses of differentially coexpressed genes. Genes related to fatty acid metabolism were retrieved from the Molecular Signatures Database (MSigDB) database. After removing duplicate genes, least absolute shrinkage and selection operator (LASSO) regression analysis, support vector machine recursive feature elimination (SVM-RFE), and random forest were applied to recognize biomarkers related to fatty acid metabolism in AVC. The CIBERSORT tool was used to analyze infiltration of immune cells in normal and AVC samples. Correlations between biomarkers and immune cells were calculated. Finally, HIBCH-related pathway was predicted by single-gene gene set enrichment analysis (GSEA). Results. 2416 differentially expressed genes and one coexpression module were identified. A total of 1473 differentially coexpressed genes were acquired. GO and KEGG enrichment analyses demonstrated that differentially coexpressed genes were closely related to fatty acid metabolism. LASSO regression analysis, SVM-REF, and random forest revealed that 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) was a biomarker of fatty acid metabolism-related genes in AVC. Significant high levels of memory B cells were found in AVC than normal samples, while activated natural killer (NK) cells were significantly low in AVC than normal samples. A significantly positive relevance was observed between HIBCH and activated NK cells, regulatory T cells, monocytes, naïve B cells, activated dendritic cells, resting memory CD4 T cells, resting NK cells, and CD8 T cells. A significantly negative relevance was observed between HIBCH and activated memory CD4 T cells, memory B cells, neutrophils, gamma delta T cells, M0 macrophages, and plasma cells. The single-gene GSEA results suggest that HIBCH may work through the inhibition of multiple immune-related pathways. Conclusion. HIBCH is closely relevant to immune cell infiltration in AVC and could be applied as a diagnostic marker for AVC.

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Plasma 3-hydroxyisobutyrate (3-HIB) and methylmalonic acid (MMA) are markers of hepatic mitochondrial fatty acid oxidation in male Wistar rats

Cited by 14 publications

References 56 publications

The Association between Non-Alcoholic Fatty Liver Disease (NAFLD) and Advanced Fibrosis with Serological Vitamin B12 Markers: Results from the NHANES 1999–2004

The Association between Non-Alcoholic Fatty Liver Disease (NAFLD) and Advanced Fibrosis with Serological Vitamin B12 Markers: Results from the NHANES 1999–2004

Phyllanthus emblica aqueous extract retards hepatic steatosis and fibrosis in NAFLD mice in association with the reshaping of intestinal microecology

Identification of HIBCH as a Fatty Acid Metabolism-Related Biomarker in Aortic Valve Calcification Using Bioinformatics

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