Asymmetric dimethylguanidino valeric acid as an independently associated risk factor for early hypertriglyceridemia and dyslipidemia

INTRODUCTION: Hypertriglyceridemia (HTG) is a crucial risk factor for cardiovascular disease, metabolic syndrome, and type 2 diabetes. However, its early detection remains challenging due to the dynamic fluctuations in plasma triglyceride levels and their limited utility in predicting long-term dyslipidemia. OBJECTIVES: This study aimed to elucidate the role of asymmetric dimethylguanidino valeric acid (ADGV) in HTG through integrated cohort analyses and mechanistic cellular experiments. METHODS: Circulating ADGV levels were quantified in a cross-sectional cohort from southern China (n = 588) and assessed its prospective association with incident HTG in an independent prospective cohort from northern China (n = 348, median follow-up: 1.8 years). Hepatocyte experiments were performed to examine biological plausibility and explore potential mechanisms linking ADGV to hepatic triglyceride metabolism. RESULTS: Elevated ADGV levels were significantly associated with increased risk of HTG and remained independently associated after adjustment for age, gender, BMI, eGFR, lifestyle factors, and liver function. Complementary in vitro studies in hepatocytes revealed that ADGV promoted triglyceride accumulation by stimulating de novo fatty acid synthesis, mediated through regulating the expression of key metabolic genes (ACC, CPT1α, and PGC1α). CONCLUSION: Higher circulating ADGV was independently associated with prevalent and incident hypertriglyceridemia across a cross-sectional cohort and an independent prospective cohort, and hepatocyte experiments support a contributory role of ADGV in hepatic lipogenesis.