Effects of Nutritional Factors on the Development of Ethanol-induced Fatty Liver in KK and KK-Ay Mice

Abstract

KK and KK-Ay mice developed a steady and reproducible fatty liver when they were given free access to an ethanol solution as a drinking fluid for 10 to 20 days. The present studies were undertaken to elucidate effects of nutritional factors on liver fat contents of the mice given water or ethanol solution. In contrast to cornstarch, sucrose tended to increase the liver fat of control mice. A higher concentration of dietary casein lowered the liver fat of control mice, whereas the dietary concentration of cottonseed oil did not significantly affect the liver rat levels either in control or ethanol groups. Thus the standard basal diets favorable for the development of the alcoholic fatty liver have been established, for example, 10% cottonseed oil, 25 and 30% casein, 58.4 and 53.4% cornstarch for KK (12-15 weeds old) and KK-Ay (5-10 weeks old), respectively. Neither choline, myoinositol, nor any lipotropic agent tested prevented the development of the alcoholic fatty liver. Unlike in rats, orotic acid did not induce a fatty liver but rather alleviated the ethanol-induced fatty liver in these mice.

Inhibition of MEK1 Signaling Pathway in the Liver Ameliorates Insulin Resistance

“…These antidiabetic effects were not due to “off-target” effects of these compounds because (i) these compounds are structurally different ( Figure 1 ), (ii) RO5126766 is specific to Raf/MEK and 10 µ mol·L −1 RO5126766 did not inhibit any of the 256 other kinases in the Ambit KINOME scan panel [ 24 , 26 ], (iii) RO4987655 is specific to MEK1/2 and 10 µ mol·L −1 RO4987655 did not inhibit any of the 400 other kinases [ 28 ], and (iv) there were no toxic signs in db/db mice treated with these compounds for 17 days (Supplemental Tables S2 and S3). These results are further supported by similar results obtained from KK-Ay mice (Supplemental Figure S2), which is another T2D model animal that has a different genetic background from db/db mice but which shows similar phenotypes, such as obesity, hyperglycemia, and hyperinsulinemia [ 35 , 36 ]. Taken together, these results strongly suggest that MEK inhibition could lower blood glucose in T2D.…”

Species Specificity of Arginine Deficiency-Induced Hepatic Steatosis

“…The susceptibility of orotic acid-in duced hepatic steatosis appears to depend on the species examined. Mice, chickens and monkeys apparently are not suscep tible to orotic acid-induced fatty livers (8)(9)(10)(11)(12). Alterations in the liver ratio of purine to pyrimidine bases were observed in both the mouse and rat fed diets con taining orotic acid (12).…”