A new fatty liver model is described in which heredity plays a major role. A marked fatty liver develo s when the homozygous mutant Zucker rat (ff or "fatty") is fe a semisynthetic diet enriched in sucrose. Lean littermates do not develop fatty livers on this experimental diet. Even old ff rats do not develop fatty livers on chow; the experimental diet is required. The fatty liver is described, including light microscopic and preliminary electron microscopic observations. The clinical importance of understanding the pathogenesis of fatty liver is obvious, and a variety of animal models have been intensively studied. In the new model described here, genetic constitution exerts a major influence. We have induced a fatty liver in a mutant rat widely used in studies of obesity since 1961, when Zucker and Zucker reported that its obesity is inherited as an autosomal Mendelian recessive trait (1). Much is known about hormonal imbalances and lipogenesis in the Zucker rat (ff or "fatty"); these features have been reviewed most recently by Bray, who compared this type of obesity with a hypothalamic model of obesity (2). In contrast, little is known about the livers of Zucker rats, either lean or ff, and we have been unable to find reports on either their light microscopic histology or their ultrastructure.The ff rats develop enormous numbers of large adipocytes but their livers do not become fatty. The fatty liver we are describing was produced in theff rats by dietary means. The diet is a semisynthetic diet to which we added 1% orotic acid to produce a fatty liver in Holtzman-Sprague-Dawley rats (3-7) and to study the effects of the hypolipidemic agent ethyl pchlorophenoxyisobutyrate (clofibrate) (8). The diet contains 60% sucrose, wt/wt, and it will be referred to as the "experimental diet." This diet was recognized by Shiff et al. (9) as Abbreviations: ATPase, adenosine triphosphatase; ER, endoplasmic reticulum; VLDL, very low density lipoprotein.producing a hyperlipidemia in Holtzman-Sprague-Dawley rats. More recently, we used the same diet in studies demonstrating: (a) that clofibrate will neutralize the orotic acid effect if fed simultaneously with the orotic acid (10); and (b) that a clofibrate + orotic acid diet will reverse an already established orotic acid-induced fatty liver (11). I was interested in studying the effects of the hyperlipidemia-inducing semisynthetic diet on the liver of a rat with congenital hyperlipidemia. This led to the development of the fatty liver model described here.
MATERIALS AND METHODSThe Zucker rats were purchased from Harriet G. Bird Memorial Laboratory, Stow, MA. A total of 6 ff and 8 lean littermate rats, 2-4 months of age and of both sexes, were fed on Purina rat chow. Five ff and 7 lean littermate rats, of the same age and of both sexes, were fed the experimental diet, for 1 week or 3 weeks. As additional controls, four 7-month-old fatties and 4 littermate leans maintained on chow were studied.The experimental diet consisted of 60% sucrose, 20% vitamin-free casein, 4...