Abstract
Background/Objectives: Cardiovascular diseases (CVD) remain the leading cause of diet-related mortality, with hepatic overproduction of very-low-density lipoprotein (VLDL) being a central driver of dyslipidemia. The microsomal triglyceride transfer protein (MTP) is essential for this process, and its activity is negatively regulated by cyclic adenosine monophosphate (cAMP). Theophylline, a methylxanthine found in tea, increases intracellular cAMP. This study aimed to evaluate whether physiologically relevant concentrations of theophylline could beneficially modulate lipoprotein secretion in an ex vivo model of diet-induced MTP activation. Methods: Primary hepatocytes were isolated from rats fed a high-fat, high-carbohydrate diet (HFCD). Cells were treated with 100 µM theophylline, and the secretion of triglyceride (TG), total cholesterol (TC), VLDL-cholesterol (VLDL-C), and HDL-cholesterol (HDL-C) was quantified. Hepatocellular MTP activity and atherogenic indices were also assessed. Results: Compared to untreated control cells, theophylline treatment significantly reduced the secretion of TG by 6% and TC by 24%. Specifically, VLDL-C secretion decreased by 6%, while HDL-C secretion increased substantially by 93%. These lipid-modulating effects were correlated with a 6.9% reduction in MTP activity. Consequently, significant improvements were observed in the atherogenic indices TG/HDL-C, TC/HDL-C, and the atherogenic index (AI) (p < 0.01). Conclusions: Our findings demonstrate that physiologically attainable concentrations of theophylline rebalance lipoprotein secretion by suppressing hepatic MTP activity, shifting the lipid profile toward an anti-atherogenic state. These results highlight the potential of theophylline as a functional dietary component for mitigating diet-induced dyslipidemia and reducing cardiovascular risk.