Biology subjects

Chen, Z.-Z.

Publications and source records attributed to Chen, Z.-Z..

4 recordsLinked to original sources

bioRxiv2026

Genetic drivers of protein changes over time: Findings, considerations, and approaches in TOPMed cohorts and UK Biobank

Age is a major risk factor for many diseases, but the biological processes driving aging are heterogeneous across individuals. Efforts to untangle differences between chronological and biological age have focused on identifying age-associated markers, such as omics clocks. Many omics features, including proteins, are strongly associated with age, and genetics contribute to variance in these measures. However, few studies have identified genetic drivers of interindividual variability in omics changes over time. Using longitudinal proteomics data (Olink 3k) from the Multi-Ethnic Study of Atherosclerosis (MESA), we calculated a protein slope for each individual (n=2,007) and protein (n=2,737) across 3 visits spanning 14-18 years, then conducted a genome-wide analysis for each slope, both with and without adjusting for baseline protein level. Subsets in UK Biobank (UKB; n=948) and CARDIA (n=1,328) with longitudinal proteomics data were used for replication. We considered additional methods for modeling of protein change and variability, including linear mixed models, SNP-by-age interactions, and variance quantitative trait loci. Without baseline adjustment, only 19 proteins (20 credible sets) had a slope pQTL in MESA, with poor replication in UKB and CARDIA. With baseline adjustment, 607 proteins (698 credivle sets) had a slope pQTL and over 70% replicated in CARDIA and/or UKB; such baseline adjusted models may, however, be subject to collider bias. Longitudinal and cross-sectional interaction models identified fewer than 14 pQTLs, suggesting they were generally underpowered; but 73% of proteins with a variance pQTL also had a slope pQTL. By examining effect direction concordance, replication rate, directed acyclic graphs, and signal overlap with other models we demonstrate that many baseline-adjusted slope pQTLs may be arising due to model misspecification or regression to the mean. Overall, our results highlight considerations for modeling strategies of change phenotypes and build on understanding of potential genetic mechanisms influencing interindividual proteome changes over time.

genetics↗

bioRxiv2025

Acute cold exposure in humans shifts the circulating proteome to a cardioprotective and anti-aging profile

Cold exposure has been proposed to provide a constellation of salutary effects, yet its molecular correlates remain largely unknown. Brown adipose tissue (BAT) is the main site of adaptive thermogenesis, and its prevalence is linked with cardiometabolic health. Since the benefits of BAT activation and cold exposure more generally may be mediated through blood-borne factors, we conducted an extensive analysis of the circulating proteome linked with an acute cold challenge in healthy adults. Our goal was to uncover early molecular changes triggered by cooling and establish their specific relationships with the human brown adipocyte secretome as well as various phenotypic traits. Based on comprehensive inter-cohort validations, we provide the first reproducible proteomic signature of cold exposure in humans. Our data demonstrate that cooling favorably modulates circulating mediators linked with chronological aging, as well as metabolic and cardiovascular diseases, providing new potential biochemical transducers of the benefits associated with cold therapy. HighlightsO_LICooling alters the plasma proteome with striking concordance in independent human cohorts. C_LIO_LICooling represses circulating proteins linked with type 2 diabetes, hypercholesterolemia, hypertension, coronary heart disease and heart failure. C_LIO_LIThe circulating signature of cooling resembles a cardioprotective and anti-aging profile. C_LI

physiology↗

bioRxiv2023

Lac-Phe mediates the anti-obesity effect of metformin

Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. The mechanisms that mediate metformins effects on energy balance remain incompletely defined. Here we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite Lac-Phe in mice as well as in two independent human cohorts. In cell culture, metformin drives Lac-Phe biosynthesis via inhibition of complex I, increased glycolytic flux, and intracellular lactate mass action. Other biguanides and structurally distinct inhibitors of oxidative phosphorylation also increase Lac-Phe levels in vitro. Genetic ablation of CNDP2, the principal biosynthetic enzyme for Lac-Phe, in mice renders animals resistant to metformins anorexigenic and anti-obesity effects. Mediation analyses also support a role for Lac-Phe in metformins effect on body mass index in humans. These data establish the CNDP2/Lac-Phe pathway as a critical mediator of the effects of metformin on energy balance.

physiology↗

bioRxiv2023

CYP4F2 is a human-specific determinant of circulating N-acyl amino acid levels

N-acyl amino acids are a large family of circulating lipid metabolites that modulate energy expenditure and fat mass in rodents. However, little is known about the regulation and potential cardiometabolic functions of N-acyl amino acids in humans. Here, we analyze the cardiometabolic phenotype associations and genetic regulation of four plasma N-fatty acyl amino acids (N-oleoyl-leucine, N-oleoyl-phenylalanine, N-oleoyl-serine, and N-oleoyl-glycine) in 2,351 individuals from the Jackson Heart Study. N-oleoyl-leucine and N-oleoyl-phenylalanine were positively associated with traits related to energy balance, including body mass index, waist circumference, and subcutaneous adipose tissue. In addition, we identify the CYP4F2 locus as a human-specific genetic determinant of plasma N-oleoyl-leucine and N-oleoyl-phenylalanine levels. In vitro, CYP4F2-mediated hydroxylation of N-oleoyl-leucine and N-oleoyl-phenylalanine results in metabolic diversification and production of many previously unknown lipid metabolites with varying characteristics of the fatty acid tail group, including several that structurally resemble fatty acid hydroxy fatty acids (FAHFAs). By contrast, FAAH-regulated N-oleoyl-glycine and N-oleoyl-serine were inversely associated with traits related to glucose and lipid homeostasis. These data uncover a human-specific enzymatic node for the metabolism of a subset of N-fatty acyl amino acids and establish a framework for understanding the cardiometabolic roles of individual N-fatty acyl amino acids in humans.

biochemistry↗