Editors' ChoiceDRUG REPURPOSING

Cholesterol Therapy That’s Not Chopped Liver

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Science Translational Medicine  12 Nov 2014:
Vol. 6, Issue 262, pp. 262ec193
DOI: 10.1126/scitranslmed.aaa2057

Here’s some extra motivation to put down that bag of chips. Although it’s common knowledge that excess alcohol consumption can harm your liver, a high-fat (HF) diet can lead to liver disease as well. Nonalcoholic fatty liver disease (NAFLD) is a condition where excess fat (triglycerides) accumulates in the liver. NAFLD comprises a spectrum of hepatic disorders in people with little or no alcohol consumption and is recognized as major health concern globally. Presently, there is no standard treatment available to address NAFLD; current therapy is limited mainly to changes in nutrition and lifestyle.

Ezetimibe (EZ) is used in the clinic to treat hypercholesteremia and acts by reducing cholesterol and liver steatosis. Cholesterol reduction takes place by inhibition of Niemann-Pick C1 Like 1–mediated cholesterol absorption at the brush border of the intestine and liver. Therefore, Wang et al. further examined the effects of EZ on liver—specifically NAFLD—using a HF-induced mouse model. Mice fed a HF diet treated with EZ demonstrated reduced serum cholesterol, hepatic fat accumulation, fibrosis, and insulin resistance in the liver compared with mice on HF diet alone. Based on expression studies, reduction was also observed in indicators for hepatic fatty acid synthesis, insulin resistance, and steatosis in the treatment group. Body weight, liver weight, and level of triglycerides were also significantly lower in the EZ-treated group in comparison with the HF group. An untreated group without HF diet could have offered as a comparative group with HF and HF+EZ groups. The authors also suggest a potential role of EZ in NAFLD-associated hepatocellular carcinoma; however, further exploration in this area is needed.

This study highlights the importance of targeted drug repurposing through understanding disease biology. It will also be interesting to establish with animal models the effect of EZ on reversing the disease condition and in individuals with a genetic predisposition.

X. Wang et al., Ezetimibe prevents the development of non-alcoholic fatty liver disease induced by high-fat diet in C57BL/6J mice. Mol. Med. Rep. 10, 2917–2923 (2014). [Full Text]

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