TY - JOUR
T1 - A novel aminosterol reverses diabetes and fatty liver disease in obese mice
AU - Takahashi, Nobuhiko
AU - Qi, Yong
AU - Patel, Hiral R.
AU - Ahima, Rexford S.
N1 - Funding Information:
The studies were supported by National Institutes of Health grant RO1-DK62348 (to R.S.A.). Technical expertise was provided by the Penn Diabetes Center Mouse Phenotyping, Physiology and Metabolism Core (P30-DK19525), and the Morphology and Molecular Biology Cores of the Center for Molecular Studies in Digestive and Liver Diseases, Division of Gastroenterology, University of Pennsylvania School of Medicine. We thank D. J. Rader (University of Pennsylvania School of Medicine) for the FPLC analysis.
PY - 2004/9
Y1 - 2004/9
N2 - Background/Aims Non-alcoholic fatty liver disease (NAFLD) is common in obesity. However, weight reduction alone does not prevent the development or progression of NAFLD. Since NAFLD is associated with insulin resistance and diabetes, we hypothesized that improvement of these factors would reverse obesity-related NAFLD. Methods We examined the effects of an aminosterol, 1436, on glucose, lipids and liver metabolism in Lepob/ob mice, a model of obesity, severe insulin resistance, diabetes, hyperlipidemia and hepatic steatosis. Results 1436 decreased body weight, specifically fat content, by inhibiting food intake and increasing energy expenditure. In contrast to weight loss from food restriction, this aminosterol specifically lowered circulating lipids, reversed hepatic steatosis and normalized alanine aminotransferase level. 1436 decreased glucose, increased adiponectin and enhanced insulin action in liver. These changes culminated in inhibition of hepatic triglyceride synthesis and increased fatty acid oxidation. Gene expression studies confirmed a reduction in lipogenic enzymes in liver, and elevation of enzymes involved in lipid catabolism. Conclusions These results demonstrate that 1436 is an effective treatment for insulin resistance and hepatic steatosis in Lep ob/ob mice, by decreasing hepatic lipid synthesis and stimulating lipolysis. In contrast, weight loss from food restriction has no substantial effect on insulin resistance, lipids and hepatic steatosis.
AB - Background/Aims Non-alcoholic fatty liver disease (NAFLD) is common in obesity. However, weight reduction alone does not prevent the development or progression of NAFLD. Since NAFLD is associated with insulin resistance and diabetes, we hypothesized that improvement of these factors would reverse obesity-related NAFLD. Methods We examined the effects of an aminosterol, 1436, on glucose, lipids and liver metabolism in Lepob/ob mice, a model of obesity, severe insulin resistance, diabetes, hyperlipidemia and hepatic steatosis. Results 1436 decreased body weight, specifically fat content, by inhibiting food intake and increasing energy expenditure. In contrast to weight loss from food restriction, this aminosterol specifically lowered circulating lipids, reversed hepatic steatosis and normalized alanine aminotransferase level. 1436 decreased glucose, increased adiponectin and enhanced insulin action in liver. These changes culminated in inhibition of hepatic triglyceride synthesis and increased fatty acid oxidation. Gene expression studies confirmed a reduction in lipogenic enzymes in liver, and elevation of enzymes involved in lipid catabolism. Conclusions These results demonstrate that 1436 is an effective treatment for insulin resistance and hepatic steatosis in Lep ob/ob mice, by decreasing hepatic lipid synthesis and stimulating lipolysis. In contrast, weight loss from food restriction has no substantial effect on insulin resistance, lipids and hepatic steatosis.
KW - ACOx, acylCoA oxidase
KW - Adiponectin
KW - Aminosterol
KW - CPT, carnitine palmitoyltransferase
KW - Diabetes
KW - FAS, fatty acid synthase
KW - GPAT, glycerol-3-phosphate acyltransferase
KW - Non-alcoholic fatty liver
KW - Obesity
KW - SREBP, sterol regulatory element-binding protein
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U2 - 10.1016/j.jhep.2004.05.006
DO - 10.1016/j.jhep.2004.05.006
M3 - Article
C2 - 15336441
AN - SCOPUS:4344566976
SN - 0168-8278
VL - 41
SP - 391
EP - 398
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 3
ER -