Proteomic profiling reveals biomarkers and pathways in type 2 diabetes risk

Ngo, Debby; Benson, Mark D.; Long, Jonathan Z.; Chen, Zsu-Zsu; Wang, Ruiqi; Nath, Anjali K.; Keyes, Michelle J.; Shen, Dongxiao; Sinha, Sumita; Kuhn, Eric; Morningstar, Jordan; Shi, Xu; Peterson, Bennet; Chan, Christopher T.; Katz, Daniel H.; Tahir, Usman A.; Farrell, Laurie; Melander, Olle; Mosley, Jonathan D.; Carr, Steven A.; Vasan, Ramachandran S.; Larson, Martin G.; Smith, J Gustav; Wang, Thomas J.; Yang, Qiong; Gerszten, Robert E.

doi:10.1172/jci.insight.144392

Cited by 31 publications

(26 citation statements)

References 71 publications

(103 reference statements)

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“…Second, N-acetylserine may be a surrogate for other ACY1 substrates, including other N-acetylated amino acids, that are harmful in excess. A recent study showed that reducing the ratio of circulating N-acetylated amino acids to free amino acids by exogenous administration of ACY1 protein acutely improves glucose tolerance in mice ( 34 ). Third, given the diverse role of protein acetylation in cellular processes, including modulation of gene expression, protein stability, and signal transduction, impaired salvage of acetyl groups could be harmful to the proximal tubule ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Metabolite profiling of CKD progression in the chronic renal insufficiency cohort study

Wen¹,

Zheng²,

Surapaneni³

et al. 2022

JCI Insight

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Background: Metabolomic profiling in individuals with chronic kidney disease (CKD) has the potential to identify novel biomarkers and provide insight into disease pathogenesis. Methods: We examined the association between blood metabolites and CKD progression, defined as the subsequent development of end-stage renal disease (ESRD) or estimated glomerular filtrate rate (eGFR) halving, in 1773 participants of the Chronic Renal Insufficiency Cohort (CRIC) study, 962 participants of the African American Study of Kidney Disease and Hypertension (AASK), and 5305 participants of the Atherosclerosis Risk in Communities (ARIC) study. Results:In CRIC, more than half of measured metabolites were associated with CKD progression in minimally adjusted Cox proportional hazards models, but the number and strength of associations were markedly attenuated by serial adjustment for covariates, particularly eGFR. Ten metabolites were significantly associated with CKD progression in fullyadjusted models in CRIC; three of these metabolites were also significant in fully-adjusted models in AASK and ARIC, highlighting potential markers of glomerular filtration (pseudouridine), histamine metabolism (methylimidazoleacetate), and azotemia (homocitrulline).Our findings also nominate N-acetylserine as a potential marker of kidney tubular function, with significant associations with CKD progression observed in CRIC and ARIC. Conclusion:Together, our findings demonstrate the application of metabolomics to identify potential biomarkers and causal pathways in CKD progression.

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Section: Discussionmentioning

confidence: 99%

Metabolite profiling of CKD progression in the chronic renal insufficiency cohort study

Wen¹,

Zheng²,

Surapaneni³

et al. 2022

JCI Insight

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“…Variants in c-MET also associate with circulating triglycerides at genome wide significance in humans consistent with a potential role for HGFAC in regulating triglyceride levels through activation of HGF (27). Moreover, increased levels of circulating HGF in people associate with features of cardiometabolic disease including obesity, risk for type 2 diabetes, and risk for cardiovascular disease (28)(29)(30)(31). Circulating HGF levels are influenced by variants in the HGFAC locus (32).…”

Section: Introductionmentioning

confidence: 99%

HGFAC is a ChREBP-regulated hepatokine that enhances glucose and lipid homeostasis

Sargsyan¹,

Doridot²,

Hannou³

et al. 2023

JCI Insight

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Carbohydrate Responsive Element-Binding Protein (ChREBP) is a carbohydrate sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating lipids. To identify novel ChREBP-regulated hepatokines that contribute to its systemic metabolic effects, we integrated ChREBP ChIP-seq analysis in mouse liver with human genetic and genomic data for lipid traits and identified Hepatocyte Growth Factor Activator (HGFAC) as a promising ChREBP-regulated candidate in mice and humans. HGFAC is a protease that activates the pleiotropic hormone Hepatocyte Growth Factor (HGF). We demonstrate that HGFAC KO mice have phenotypes concordant with putative loss-of-function variants in human HGFAC. Moreover, in gain-and loss-of-function genetic mouse models, we demonstrate that HGFAC enhances lipid and glucose homeostasis, which may be mediated in part through actions to activate hepatic PPARγ activity. Together, our studies show that ChREBP mediates an adaptive response to overnutrition via activation of HGFAC in the liver to preserve glucose and lipid homeostasis. 4 manner and participates in an adaptive response maintaining carbohydrate and lipid homeostasis. Results: HGFAC is a ChREBP genomic target associating with metabolic traits in humansTo identify ChREBP transcriptional targets that participate in the regulation of ChREBP associated metabolic programs and phenotypes, we performed ChIP-seq analysis for ChREBP in livers of two strains of male mice gavaged with either water or fructose. We identified 4,860 distinct genomic sites enriched for ChREBP binding (Supplementary Table 1) which include well-defined loci in canonical ChREBP targets involved in glycolysis, glucose production, fructolysis, and lipogenesis such as liver pyruvate kinase (PKLR), glucose-6-phosphatase (G6PC), fatty acid synthase (FASN), and ketohexokinase (KHK), respectively (Figure 1A). Although fructose gavage can acutely induce ChREBP-dependent changes in gene expression, ChREBP ChIP-seq peaks were readily detectable in fasted mice, and fructose gavage did not enhance ChREBP ChIP-seq peak height even at a liberal false discovery rate of 0.20. This indicates that increased chromatin occupancy is not essential for fructose to induce ChREBP-dependent gene transcription. Most ChREBP ChIP peaks occurred within 10 kb of transcriptional start sites (Figure 1B). Consistent with ChREBP's known functions, Genomic Region Enrichment Analysis (GREAT) of putative ChREBP binding sites demonstrated enrichment for numerous metabolic processes including carbohydrate and lipid metabolism (Figure 1C) (18).Variants in the ChREBP locus are strongly associated with hypertriglyceridemia in human populations (19,20). However, the complement of ChREBP transcriptional targets that mediate its effects on circulating lipids is uncertain. We sought to determine whether genomic loci containing human homologues of...

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“…A recent study has described a strong positive correlation between ACY1 protein levels and type 2 diabetes (T2DM). 45 Through in vitro and in vivo experiments, the authors showed that increasing amounts of ACY1 decreased the ratio of N-acetyl/free amino acids, with a consequent effect on glucose and insulin homeostasis, possibly leading to b-cell exhaustion, reduced b-cell mass, and ultimately insulin deficiency and T2DM. In another recent study in a subset of participants from the INTERVAL study, a polygenic risk score for T2DM was associated with ACY1 protein levels, thus strengthening the link between ACY1 and T2D risk.…”

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing identifies rare genetic variants associated with human plasma metabolites

Bomba

Walter

Guo

et al. 2022

The American Journal of Human Genetics

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Proteomic profiling reveals biomarkers and pathways in type 2 diabetes risk

Cited by 31 publications

References 71 publications

Metabolite profiling of CKD progression in the chronic renal insufficiency cohort study

Metabolite profiling of CKD progression in the chronic renal insufficiency cohort study

HGFAC is a ChREBP-regulated hepatokine that enhances glucose and lipid homeostasis

Whole-exome sequencing identifies rare genetic variants associated with human plasma metabolites

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