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Biochemistry Research International
Volume 2012, Article ID 135723, 11 pages
Research Article

The Increased Activity of Liver Lysosomal Lipase in Nonalcoholic Fatty Liver Disease Contributes to the Development of Hepatic Insulin Resistance

1Department of Metabolism and Diabetes, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague 4, Czech Republic
2Diabetes Center, Institute for Clinical and Experimental Medicine, 14021 Prague 4, Czech Republic
3Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, OR 97239-3098, USA
4Department of Medicinal and Clinical Chemistry, University of Heidelberg, 69117 Heidelberg, Germany
5Laboratory of Experimental Hepatology, Institute for Clinical and Experimental Medicine, 14021 Prague 4, Czech Republic

Received 4 March 2011; Revised 10 May 2011; Accepted 2 June 2011

Academic Editor: Todd B. Reynolds

Copyright © 2012 Monika Cahova et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


We tested the hypothesis that TAG accumulation in the liver induced by short-term high-fat diet (HFD) in rats leads to the dysregulation of endogenous TAG degradation by lysosomal lipase (LIPA) via lysosomal pathway and is causally linked with the onset of hepatic insulin resistance. We found that LIPA could be translocated between qualitatively different depots (light and dense lysosomes). In contrast to dense lysosomal fraction, LIPA associated with light lysosomes exhibits high activity on both intracellular TAG and exogenous substrate and prandial- or diet-dependent regulation. On standard diet, LIPA activity was upregulated in fasted and downregulated in fed animals. In the HFD group, we demonstrated an increased TAG content, elevated LIPA activity, enhanced production of diacylglycerol, and the abolishment of prandial-dependent LIPA regulation in light lysosomal fraction. The impairment of insulin signalling and increased activation of PKCε was found in liver of HFD-fed animals. Lipolysis of intracellular TAG, mediated by LIPA, is increased in steatosis probably due to the enhanced formation of phagolysosomes. Consequent overproduction of diacylglycerol may represent the causal link between HFD-induced hepatic TAG accumulation and hepatic insulin resistance via PKCε activation.