Effect of diosgenin on lipid metabolism in rats

The purpose of this study was to determine whether diosgenin suppresses cholesterol absorption in rats, and to examine relevant changes in cholesterol and bile acid metabolism. Diosgenin fed with the diet for 1 week inhibited cholesterol absorption as determined by the serum isotope ratio technique, as well as by measuring in the feces the amount of unabsorbed radioactivity from orally administered [3H]cholesterol. In addition, diosgenin suppressed the serum and liver uptake of radioactivity from co-administered [3H]cholesterol as well as the accumulation of liver cholesterol in the cholesterol-fed rat; diosgenin was substantially more active than cholestyramine or p-sitosterol. In vitro, diosgenin had no effect on the activity of rat pancreatic esterase. Diosgenin decreased the elevated cholesterol in serum LDL and elevated cholesterol in the HDL fraction of cholesterol-fed rats; diosgenin had no effect on serum cholesterol in normocholesterolemic rats. In contrast to cholestyramine, diosgenin markedly increased neutral sterol excretion without altering bile acid excretion; in vitro, diosgenin had no effect on bile acid binding. Diosgenin treatment increased hepatic and intestinal cholesterol synthesis as well as the activity of hepatic HMG CoA reductase. This was accompanied by increased biliary concentration of cholesterol, but not of bile acids. Diosgenin had no effect on cholesterol synthesis when added to normal rat liver homogenates. It was concluded that diosgenin interferes with the absorption of cholesterol of both exogenous and endogenous origin; such interference is accompanied by derepressed, Le., increased, rates of hepatic and intestinal cholesterol synthesis. The increased unabsorbed cholesterol together with enhanced secretion of cholesterol into bile resulted in increased excretion of neutral sterols without affecting the biliary and fecal excretion of bile acids. Cayen, M. N., and D. Dvomik. Effect of diosgenin on lipid metabolism in rats.]. Lzpid Res. 1979. 20: 162-174. Supplementary key words cholesterol . triglycerides . bile acids . p-sitosterol * cholestyramine . HMG CoA reductase . liver . intestine Hypercholesterolemia is generally accepted as an independent risk factor contributing to the development of coronary heart disease (1). While controlled treatment, e.g., by clofibrate (3); however, the control by drugs of elevated levels of low density lipoproteins (LDL) is not always satisfactory. At the present time, anion exchange resins are more often used to treat hypercholesterolemia (3). The resins lower plasma cholesterol by binding bile acids in the gastrointestinal tract (4), thereby increasing the rate of cholesterol catabolism (5) andlor suppressing sterol absorption (6). However, because of high dosage, the resins are not ideal for chronic treatment. An interesting alternative treatment of hyperbetalipoproteinemia is based on the use of agents that would interfere with cholesterol absorption directly, such as p-sitosterol (7), saponins (a), and sulfaguanidine (9). In our search for such compounds, we have found that the Solanum glycoside tomatine inhibits cholesterol absorption in rats and markedly enhances the excretion of neutral sterols without affecting that of bile acids (IO). Prompted by this finding, we were interested to determine whether the sugar moiety was required for this activity. Because of the scarcity of tomatidine, the aglycone of tomatine, we have worked with the more readily available diosgenin (Fig. l), a sapogenin structurally similar to tomatidine. Diosgenin had been reported to lower serum cholesterol in chickens and rabbits fed cholesterol (11) and to decrease liver cholesterol in cholesterol-fed rats (12). We have investigated the effect of orally administered diosgenin on cholesterol absorption in normal rats; since it was active, we have examined in some detail the effects of diosgenin on cholesterol and bile acid metabolism in the rat.' During the course of our investigations, Zagoya, Laguna, and Guzman-Garcia (1 5) reported that, in vitro, diosgenin inhibited cholesterol uptake in an everted gut preparation and, in vivo, it enhanced