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Iron loading is associated with altered lipid metabolism, but underlying mechanisms remain unknown. We compared serum iron and triglycerides (TGs) in Belgrade rats, a genetic model of iron-loading anemia. Homozygous b/b rats had greater serum iron (68 vs. 28 μM; P=0.0004) and TG levels (180 vs. 84 mg/dl; P=0.014) compared to +/b controls. To confirm the association between iron loading and high TGs, Fischer rats were fed chow containing 1% carbonyl iron. Compared to controls pair-fed normal chow, carbonyl iron-fed rats had elevated serum iron (42 vs. 21 μM; P=0.007) and TGs (190 vs. 115 mg/dl; P=0.009). Despite normal hepatic production and secretion, TG clearance was lower in b/b than +/b rats due to reduced serum lipoprotein lipase (LPL) activity (3.1 vs. 5.0 mM/min; P=0.026). Likewise, LPL was lower in carbonyl iron-fed rats compared to controls (2.4 vs. 3.7 mM/min; P=0.017). Direct addition of iron to serum ex vivo or recombinant LPL in vitro decreased enzymatic activity in a dose-dependent manner. Lowering serum iron in Belgrade rats reduced TG levels (274 to 67 mg/dl, P=0.001). This study explains the relationship between iron status and lipid metabolism and provides mechanistic support for interventions that reduce serum iron levels in individuals at risk for hypertriglyceridemia. [ABSTRACT FROM AUTHOR]