Previous studies conducted under basal conditions have suggested a linkage between the formation of plasma triglyceride and the degradation of cholesterol to bile acids. To further examine this relationship, plasma endogenous triglyceride kinetics were determined using [(3)H]glycerol in 26 hyperlipidemic subjects before and during stimulated (cholestyramine treatment) and inhibited (chenodeoxycholic acid treatment) bile acid synthesis. All patients with hyperlipoproteinemia (HLP) type II (n = 9) treated with cholestyramine (12 g daily for 2-4 months) displayed increased apparent biosynthesis (12.8 +/- 1.5 vs. 9.7 +/- 1.2 micro mol kg(-1)hr(-1), mean +/- SEM, P < 0.005) and an elevated apparent fractional turnover rate (0.230 +/- 0.017 vs. 0.176 +/- 0.014 hr(-1), P < 0.001) as determined over a 10-hr period, in spite of essentially unchanged plasma triglyceride concentrations. No consistent effect of this therapy was encountered in the five patients studied with type IV HLP. Chenodeoxycholic acid feeding (1.9 mmol daily for 3-4 months) resulted in a reduced apparent synthesis of plasma triglycerides both in type IIa (n = 5, 7.9 +/- 0.5 vs. 13.1 +/- 1.2 micro mol kg(-1)hr(-1), P < 0.01) and type IV HLP (n = 7, 15.5 +/- 1.8 vs. 23.6 +/- 3.7 micro mol kg(-1)hr(-1), P < 0.02). Furthermore, a 20-25% reduction of the apparent fractional turnover rate was seen, and the plasma concentration of triglycerides was reduced by about 15%. It is concluded that the present experimental conditions that primarily influence cholesterol and bile acid biosynthesis also affect the metabolism of plasma triglycerides-and presumably that of very low density lipoprotein-in a regulatory manner. Hypothetically, this may be achieved via a hepatic pool of newly synthesized cholesterol.