Objective: The exact relationship between the serum uric acid-to-HDL cholesterol ratio (UHR) and mortality rates remains enigmatic among American adults. This study aims to clarify the association between UHR and both all-cause and cardiovascular disease (CVD) mortality in US adults.Methods: This study enrolled 48054 patients from the National Health and Nutrition Examination Survey (NHANES). Mortality outcomes were determined by linking to National Death Index (NDI) records up to December 31,2019. Multivariate Cox proportional hazards models were constructed to analyze explore the associations between UHR and mortality. Dose-response relationships were explored using restricted cubic splines, and stratified analyses were conducted based on gender, age, race, education, PIR, smoking status, alcohol intake, physical activity, BMI, diabetes and hypertension.Results: During the follow-up period, the overall mortality for all-cause and CVD was 10.9% and 2.7%, respectively. The adjusted HRs in the highest quintile were 1.16 (95% CI: 1.05, 1.29) for all-cause mortality and 1.2 (95% CI: 1, 1.45) for CVD mortality. In diabetes, obese, and CVD subgroups, significantly elevated adjusted HRs were observed for both all-cause and CVD mortality. Specifically, diabetes patients had adjusted HRs of 1.32 (95% CI: 1.11, 1.57) and 1.38 (95% CI: 1.01, 1.90), obese individuals had HRs of 1.32 (95% CI: 1.10, 1.58) and 1.55 (95% CI: 1.06, 2.28), and CVD patients had HRs of 1.29 (95% CI: 1.10, 1.50) and 1.38 (95% CI: 1.06, 1.79), respectively. A non-linear relationship between UHR and mortality was identified, with critical thresholds of 12.4 for all-cause mortality and 10.7 for CVD mortality in the general population. Significant interactions were observed between UHR and stratified variables, including gender, BMI, education, smoking, alcohol use, and hypertension for all-cause mortality, while significant interactions were observed based on gender, smoking, and alcohol intake for CVD mortality. Comparable trends were also observed in patient with diabetes, obese and CVD.Conclusions: In this cohort study, we provide novel insights into the association between serum UHR concentrations and mortality in the general population. UHR is a strong predictor of all-cause and cardiovascular mortality in the general population.

Under normal conditions, insulin promotes hepatic de novo lipogenesis (DNL). However, during insulin resistance (IR), when insulin signalling is blunted and accompanied by hyperinsulinaemia, the promotion of hepatic DNL continues unabated and hepatic steatosis increases. Here, we show that WD40 repeat-containing protein 6 (WDR6) promotes hepatic DNL during IR. Mechanistically, WDR6 interacts with the beta-type catalytic subunit of serine/threonine-protein phosphatase 1 (PPP1CB) to facilitate PPP1CB dephosphorylation at Thr316, which subsequently enhances fatty acid synthases transcription through DNA-dependent protein kinase and upstream stimulatory factor 1. Using molecular dynamics simulation analysis, we find a small natural compound, XLIX, that inhibits the interaction of WDR6 with PPP1CB, thus reducing DNL in IR states. Together, these results reveal WDR6 as a promising target for the treatment of hepatic steatosis.

Metabolic disorders are classified clinically as a complex and varied group of diseases including metabolic syndrome, obesity, and diabetes mellitus. Fat toxicity, chronic inflammation, and oxidative...

Background: The correlation between white cell count and metabolically healthy obesity (MHO) remains elusive among obese American adults. This study endeavors to elucidate this association.Methods: This study enrolled 6,580 obese patients from the National Health and Nutrition Examination Survey (NHANES). Obesity phenotypes were defined by presence/absence of metabolic syndrome components. Weighted multivariate logistic regression analyses were used to assess the association between white cell count and MHO occurrence. Restricted cubic spline analysis characterized dose–response relationships, and stratified analyses explored these relationships across sociodemographic and lifestyle factors.Results: In this study, MHO prevalence is 11.9% among obese adults. The risk of MHO was inversely correlated with WBC [OR (95%): 0.81 (0.76, 0.86), p < 0.001], lymphocytes [OR (95%): 0.56 (0.47, 0.68), p < 0.001], monocytes [OR (95%): 0.41 (0.22, 0.75), p = 0.004], and neutrophils count [OR (95%): 0.82 (0.76, 0.88), p < 0.001]. WBC and neutrophils showed L-shaped associations, while lymphocytes, monocytes, and RBCs had linear patterns. Furthermore, stratified analyses demonstrated blood cell counts consistently predicted MHO risk across subgroups.Conclusion: In this study, we provide novel insights into the association between blood cell count and the presence of MHO among obese individuals. Blood cell count is an accessible biomarker for dynamically tracking the presence of MHO.

The link between gastroesophageal reflux disease (GERD) and essential hypertension (EH) and its causal nature remains controversial. Our study examined the connection between GERD and the risk of hypertension and assessed further whether this correlation has a causal relationship. First, we utilized the National Readmission Database including 14 422 183 participants to conduct an observational study. Dividing the population into GERD and non-GERD groups, we investigated the correlation between GERD and EH using multivariate logistic regression. Next, bidirectional two-sample Mendelian randomization was adopted. The summary statistics for GERD were obtained from a published genome-wide association study including 78 707 cases and 288 734 controls. We collected summary statistics for hypertension containing 70 651 cases and 223 663 controls from the FinnGen consortium. We assessed causality primarily by the inverse-variance weighted method with validation by four other Mendelian randomization approaches as well as an array of sensitivity analyses. In the unadjusted model, GERD patients had a higher risk of EH than the non-GERD group, regardless of gender (odds ratio, 1.43; 95% confidence interval: 1.42–1.43; P < .001). Further adjusting for critical confounders did not change this association. For Mendelian randomization, we found that genetically predicted GERD was causally linked to an enhanced risk of EH in inverse-variance weighted technique (odds ratio, 1.52; 95% confidence interval: 1.39–1.67; P = 3.51 × 10⁻¹⁸); conversely, EH did not raise the risk of GERD causally. GERD is a causal risk factor for EH. Further research is required to probe the mechanism underlying this causal connection. What is already known on this topic GERD can increase the risk of hypertension and increase with worsening disease severity. The association between GERD and EH and whether the link is genetically determined are still controversial. What this study adds Our study revealed that GERD is an upstream causal risk factor for EH. How this study might affect research, practice, or policy Preventing GERD may serve as a prevention policy for EH.

Background: The mammalian liver executes its vital functions through intricate hepatic biochemistry. However, the complexity of the liver metabolome and its dynamic alterations during metabolic dysfunction-associated steatotic liver disease (MASLD) remain poorly understood. Methods: We established progressive MASLD mouse models through high-fat diet (HFD) and high-fat/high-cholesterol (HFHC) dietary-feeding across multiple time points. Utilizing liquid chromatography-mass spectrometry (LC-MS)-based metabolomics and lipidomics, we systematically mapped the metabolome atlas of the mouse liver across five anatomical segments during the progression of MASLD. Results: By integration of data from two assays, we structurally annotated 426 lipids and 118 polar metabolites. The temporal progression of HFD feeding (0, 8, and 16 weeks) resulted in gradual metabolic deterioration across various liver segments. In HFHC-fed mice, metabolic alterations surged sharply from 0 to 8 weeks, followed by moderate progression until 16 weeks in different liver segments. Elevated levels of glycerolipids and cholesteryl esters, along with fluctuating acylcarnitine and fatty acid levels across various liver segments, suggested impaired energy metabolism and disrupted fatty acid oxidation. As MASLD progresses, a shift in sphingolipid metabolism, linked to inflammation, was observed, accompanied by significant alterations in phospholipid turnover patterns. Additionally, amino acid profiles in the livers of HFD-fed and HFHC-fed mice were altered, potentially influencing the regulation of energy metabolism, inflammation, and oxidative stress. These metabolic changes in lipids and amino acids displayed segment-specific patterns, indicating varying sensitivities to inflammation and mitochondrial β-oxidation across different liver lobes. Notably, the left lateral lobe showed heightened sensitivity to metabolic disturbances during MASLD progression. Conclusion: Our findings provided in-depth understanding in hepatic metabolites of MASLD, offering a comprehensive resource for further investigation.