Comparative Changes in the Liver of Female Fischer-344 Rats after Short-Term Feeding of a Semipurified or a Semisynthetic L-Amino Acid-Defined Choline-Deficient Diet

Abstract

Groups of female Fischer-344 rats were fed a semipurified choline-deficient (CD) diet, or a semisynthetic L-amino acid-defined choline-deficient (CDAA) diet, for up to 12 wk and effects of the 2 diets on the liver were compared. Steatosis was diffuse and more severe throughout in rats fed the CDAA diet than in rats fed the CD diet. Greater elevations in serum aspartate and alanine aminotransferase activities were also present in the former rats, along with higher 2-bromodeoxyuridine labeling indices in the liver. Discrete amounts of 8-hydroxyguanine were detected in liver DNA, but were not significantly different in rats fed the 2 diets, or from those present in a group of control rats killed at 0 time. Glutathione S-transferase placental formpositive focal lesions were not observed in any of the rats. The results show that the CDAA diet causes more severe degrees of steatosis and liver cell death and proliferation than the CD diet, raising the possibility that it may, in contrast to the CD diet, result in the eventual induction of hepatocellular carcinomas in female Fischer-344 rats.

Development of Hepatocellular Adenomas and Carcinomas Associated with Fibrosis in C57BL/6J Male Mice Given a Choline‐deficient, L‐Amino Acid‐defined Diet

“…Our results also point to a relative resistance of C57BL/ 6J females compared with males, which also holds true for rats. [35][36][37] In humans, the development of cirrhosis, HCCs and HCCs in cirrhosis is known to be more frequent in men than women. 38,39) Sexual dimorphism in various functions of the liver is well known and the liver possesses nuclear and cytosolic estrogen receptors.…”

Animal Models of Nonalcoholic Steatohepatitis: Eat, Delete, and Inflame

“…CDAA diet has the same overall composition as the choline deficient (CD) diet, but proteins are replaced with an equivalent and corresponding mixture of L-amino acids [40]. Like the MCD diet, it inhibits fatty acid oxidation in hepatocytes, increases lipid synthesis, oxidative stress and inflammation, resulting in liver fibrosis [41], but requires a longer time frame than MCD diet for these histological changes to develop [40].…”

“…Like the MCD diet, it inhibits fatty acid oxidation in hepatocytes, increases lipid synthesis, oxidative stress and inflammation, resulting in liver fibrosis [41], but requires a longer time frame than MCD diet for these histological changes to develop [40]. Mice on the CDAA diet do not display hepatic insulin resistance [39], nor do they gain weight or have changes in peripheral insulin sensitivity.…”

Endogenous liver carcinogenesis in the rat *

“… 28–30 This is particularly apparent when the diets are administered to female Fischer 344 rats, which are largely resistant, for as yet undefined reasons, to the acute hepatic effects of the CD diet and in turn do not develop HCC. 63–66 During a 12‐week feeding of the CDAA diet, in contrast, diffuse fatty liver with the increase of liver content of triglyceride, hepatocyte deaths with the increase of serum ALT activity and regenerative hepatocyte proliferation are induced in such rats. 66 In addition, we recently observed HCC development in the cirrhotic livers of female Fischer 344 rats fed the CDAA diet for over 1 year, albeit with a lower incidence than obtained in the male case.…”

“… 63–66 During a 12‐week feeding of the CDAA diet, in contrast, diffuse fatty liver with the increase of liver content of triglyceride, hepatocyte deaths with the increase of serum ALT activity and regenerative hepatocyte proliferation are induced in such rats. 66 In addition, we recently observed HCC development in the cirrhotic livers of female Fischer 344 rats fed the CDAA diet for over 1 year, albeit with a lower incidence than obtained in the male case. The question as to why the CDAA diet exerts greater effects than the CD diet remains unanswered.…”