Background and Aims: Little is known about the relationships between lipoprotein subtypes and the risk of cardiovascular disease (CVD) in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD). We sought to elucidate the associations of lipoprotein subclasses with the risk of CVD in individuals with MASLD.

Methods and Results: This study included 51,472 individuals with MASLD from the UK biobank. Concentrations of lipoprotein subclasses were quantified by nuclear magnetic resonance (NMR). Multivariable-adjusted Cox proportional hazards model was used to evaluate the associations between lipoprotein subclasses and the incidence/mortality of CVD. During a median follow-up of 13.3-13.5 years, 6,208 incident cases of CVD, 5,206 CHD cases, 1,207 stroke cases, and 559 CVD-related deaths were documented in UK Biobank. Most VLDL [hazard ratio (HR) range: 1.03-1.13; P <0.05], IDL (HR range: 1.07-1.10; P <0.05), LDL (HR range: 1.06-1.11; P <0.05), very large HDL particles and triglycerides in small HDL subclasses (HR range: 1.03-1.10; P <0.05) were positively associated with the risk of incident CVD, whereas other HDL particles and their subclasses were related to reduced risks of CVD risks (HR range: 0.88-0.96; P <0.05).

Conclusion: These findings suggest that associations between lipoprotein subclasses and the risk of CVD differed by particle diameter. Moreover, the association with CVD strengthened as the diameter of VLDL decreased. The role of HDL subclasses in CVD risks, as either risk or protective factors, is determined by particle size rather than lipid composition.