Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2ß1.

Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2ß1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2ß1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis.

Upregulation of Superenhancer-Driven LncRNA FASRL by USF1 Promotes De Novo Fatty Acid Biosynthesis to Exacerbate Hepatocellular Carcinoma.

Superenhancers drive abnormal gene expression in tumors and promote malignancy. However, the relationship between superenhancer-associated long noncoding RNA (lncRNA) and abnormal metabolism is unknown. This study identifies a novel lncRNA, fatty acid synthesis-related lncRNA (FASRL), whose expression is driven by upstream stimulatory factor 1 (USF1) through its superenhancer. FASRL promotes hepatocellular carcinoma (HCC) cell proliferation in vitro and in vivo. Furthermore, FASRL binds to acetyl-CoA carboxylase 1 (ACACA), a fatty acid synthesis rate-limiting enzyme, increasing fatty acid synthesis via the fatty acid metabolism pathway. Moreover, the expression of FASRL, USF1, and ACACA is increased, and their high expression indicates a worse prognosis in HCC patients. In summary, USF1 drives FASRL transcription via a superenhancer. FASRL binding to ACACA increases fatty acid synthesis and lipid accumulation to mechanistically exacerbate HCC. FASRL may serve as a novel prognostic marker and treatment target in HCC.

Association of Plasma Connective Tissue Growth Factor Levels with Hyperthyroid Heart Disease.

Hyperthyroid heart disease (HHD) is one of the most severe complications of overt hyperthyroidism and increases the risk of mortality in affected patients. Early identification of patients at a higher risk of developing HHD can improve clinical outcomes through active surveillance and management. Connective tissue growth factor (CTGF), a secreted extracellular protein, plays a significant role in cardiac remodeling and dysfunction. We aimed to investigate the association between plasma CTGF level and the risk of HHD in this study. A total of 142 overt hyperthyroid patients without HHD and 99 patients with HHD were included. The plasma CTGF levels were measured using ELISA kits. Routine clinical medical data and echocardiography parameters were recorded for analysis. The plasma CTGF level was significantly higher in patients with HHD than in those without HHD (P=0.002). The plasma CTGF level was positively correlated with free triiodothyronin, tryrotropin receptor antibody, troponin I and lactate dehydrogenase levels and the left atrium diameters, right atrium diameters, and right ventricular end-diastolic diameters (all P<0.05). Logistic regression analysis showed that quartiles 3 and 4 of plasma CTGF levels were significantly associated with the increased risk of HHD (crude OR: 2.529; 95% CI: 1.188-5.387). However, after adjustment for the potentially confounding variables, quartile 4 alone was significantly associated with the higher risk of HHD relative to quartile 1. Hyperthyroid patients with HHD display higher plasma CTGF levels. Furthermore, CTGF is an independent risk factor for HHD. Therefore, the plasma CTGF level may be a potential biomarker for the risk of HHD.

Prevalence and Risk Factors of Left Ventricular Diastolic Dysfunction in Patients With Hyperthyroidism.

Background: Left ventricular (LV) diastolic dysfunction has been demonstrated to be an independent predictor of the future heart failure. Heart failure is one of the severe complications caused by overt hyperthyroidism. However, the effects of overt hyperthyroidism on diastolic dysfunction are conflicting, and little is known about the prevalence and risk factors of the diastolic dysfunction in patients with overt hyperthyroidism. Methods: A total of 388 patients with overt hyperthyroidism were included and compared with 388 age- and gender- matched euthyroid control subjects. LV diastolic function was evaluated by traditional and tissue-Doppler echocardiography. Routine clinical medical data and echocardiographic parameters were recorded for analysis. Results: The prevalence of LV diastolic dysfunction was 35.1% among hyperthyroid patients and significantly higher than control subjects whose prevalence was 25.5% (P = 0.003), and it increased with age and body mass index (BMI) in patients with overt hyperthyroidism. The possible risk factors for LV diastolic dysfunction, such as hypertension, diabetes, decreased estimated glomerular filtration rate (eGFR), and increased level of thyroid hormones weren't associated with LV diastolic dysfunction. However, overweight or obese were significantly associated with LV diastolic dysfunction (OR = 3.024, 95% CI = 1.517-6.027, P = 0.002) compared with normal BMI. When compared with age <40 years old group, 40-50 years old group, 50-60 years old group and age ≥60 years old group were significantly associated with LV diastolic dysfunction, with ORs of 2.976 (95% CI = 1.744-5.019), 12.424 (95% CI = 4.934-31.283), 24.966 (95% CI = 5.975-104.321), respectively. Conclusion: LV diastolic dysfunction was very common, in particular, in older and overweight or obese patients with overt hyperthyroidism. Additionally, age and BMI were independent risk factors for LV diastolic dysfunction, while the level of thyroid hormones was not. Therefore, besides the LV systolic function, we also need focus on the diastolic function in patients with overt hyperthyroidism in clinical work, especially the older and overweight or obese patients.