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Potential Approaches to Ameliorate Hepatic Fat Accumulation Seen with MTP Inhibition

Drug Safety volume 37, pages 213–224 (2014)Cite this article

Abstract

Microsomal triglyceride transfer protein (MTP) is one of the promising targets for the therapy of dyslipidemia and MTP inhibition can lead to robust plasma low-density lipoprotein cholesterol (LDL-C) reduction. Lomitapide, a small-molecule MTP inhibitor, was recently approved by the US FDA as an additional treatment for homozygous familial hypercholesterolemia (hoFH). However, liver-related side effects, including hepatic fat accumulation and transaminase elevations, are the main safety concerns associated with MTP inhibitors. Here, we review recent knowledge on the mechanisms underlying liver toxicity of MTP inhibitors. The contribution of altered levels of intracellular triglycerides, cholesteryl esters, and free cholesterols toward cellular dysfunction is specifically addressed. On this basis, therapies targeted to attenuate cellular lipid accumulation, to reduce risk factors for non-alcoholic fatty liver disease (NAFLD) (i.e., insulin resistance and oxidative stress) and to specifically inhibit intestinal MTP may be useful for ameliorating liver damage induced by MTP inhibitors. In particular, weight loss through lifestyle interventions is expected to be the most effective and safest way to minimize the undesirable side effects. Specific dietary supplementation might also have protective effects against hepatosteatosis. Despite that, to date, few clinical data support these therapeutic options in MTP inhibition-related liver damage, such proposed approaches may be further explored in the future for their use in preventing unwanted effects of MTP inhibitors.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (Project 81170262), National Program on Key Basic Research Project of China (973 Program) (No. 2012CB517504) and the Fundamental Research Funds for the Central Universities of Central South University (No.2013zzts325) (to L.M.J).

Conflict of interest

Minjie Lin, Shuiping Zhao, Li Shen, and Danyan Xu have no conflicts of interest that are directly relevant to the content of this article.

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  1. Department of Cardiology, Second Xiangya Hospital, Central South University, Changsha, 410011, People’s Republic of China

    Minjie Lin, Shuiping Zhao, Li Shen & Danyan Xu

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Lin, M., Zhao, S., Shen, L. et al. Potential Approaches to Ameliorate Hepatic Fat Accumulation Seen with MTP Inhibition. Drug Saf 37, 213–224 (2014). https://doi.org/10.1007/s40264-014-0147-x

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Keywords

  • Metformin
  • NASH
  • Hepatic Steatosis
  • Ezetimibe
  • Free Cholesterol