Abstract
The iminosugar N-(5′-adamantane-1′-yl-methoxy)-pentyl-1-deoxynoijirimycin (AMP-DNM), an inhibitor of glycosphingolipid (GSL) biosynthesis is known to ameliorate diabetes, insulin sensitivity and to prevent liver steatosis in ob/ob mice. Thus far the effect of GSL synthesis inhibition on pre-existing NASH has not yet been assessed. To investigate it, LDLR(−/−) mice were kept on a western-type diet for 12 weeks to induce NASH. Next, the diet was continued for 6 weeks in presence or not of AMP-DNM in the diet. AMP-DNM treated mice showed less liver steatosis, inflammation and fibrosis. Induction of fatty acid beta-oxydation was observed, as well as a reduction of plasma lipids. Our study demonstrates that AMP-DNM treatment is able to significantly correct pre-existing NASH, suggesting that inhibiting GSL synthesis may represent a novel strategy for the treatment of this pathology.
Highlights
The metabolic syndrome represents a combination of health risk factors including abdominal obesity, insulin resistance, dyslipidemia and hypertension
We have previously demonstrated in leptin-deficient ob/ob mice that AMP-DNM treatment reduced liver steatosis associated with a restoration of liver insulin signaling [9]
A limitation of the leptin-deficient ob/ob and dietinduced obesity (DIO) models is that the mice do not develop steatohepatitis or liver fibrosis as is observed in humans [21]
Summary
The metabolic syndrome represents a combination of health risk factors including abdominal obesity, insulin resistance, dyslipidemia and hypertension. Non Alcoholic Fatty Liver Disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NALFD includes a large variety of liver derangements ranging from simple fat accumulation in the parenchymal cells (steatosis) to non-alcoholic steatohepatitis (NASH) including inflammation and varying degrees of fibrosis. It is expected that as the prevalence of obesity and metabolic syndrome rises, NAFLD-associated diseases will be an increasing healthcare concern and therapeutic measures are needed to address this major health problem [4,5]. Fat accumulation in hepatocytes is the result of an imbalance between triglyceride synthesis and degradation. An increased flux and/or endogenous synthesis of free fatty acids (FFA) may lead to accumulation of triglycerides within the liver when mitochondrial b-oxidation and VLDL production and secretion are not sufficient to handle the FFA load. Hepatic inflammatory cell recruitment and inflammatory cytokines appear to play a key role in this process and dietary cholesterol has been proposed to be an important contributor for the development of the pathology in hyperlipidemic mouse models [6,7]
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