Article thumbnail

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

By Monika Cahova, Helena Dankova, Eliska Palenickova, Zuzana Papackova, Radko Komers, Jana Zdychova, Eva Sticova and Ludmila Kazdova

Abstract

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

Topics: Research Article
Publisher: Hindawi Publishing Corporation
OAI identifier: oai:pubmedcentral.nih.gov:3163129
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles

Citations

  1. (1957). A simple method for the isolation and purification of total lipides from animal tissues,”TheJournalofBiologicalChemistry,vol.226,no.1,pp. 497–509,
  2. (1997). Alterations in the expression and cellular localization of protein kinaseCisozymesεandθ areassociatedwithinsulinresistance in skeletal muscle of the high-fat-fed rat,”
  3. (2010). Autophagy in health and disease. 2. Regulation of lipid metabolism and storage by autophagy: pathophysiological implications,”
  4. (2009). Autophagy regulates lipid metabolism,”
  5. (1990). Biosynthesis, processing, and intracellular transport of lysosomal acid phosphatase in rat hepatocytes,”
  6. Daˇ nkov´ a, E. P´ alen´ ıˇ ckov´ a, Z. Pap´ aˇ ckov´ a, and L. Kazdov´ a, “The autophagy-lysosomal pathway is involved in TAG degradation in the liver: the effect of high-sucrose and high-fatdiet,”FoliaBiologica,vol.56,no.4,pp.173–182,2010.
  7. (1971). Effect of glucagon, catecholamines and insulin on liver acid lipase and acid phosphatase,”
  8. (1996). Hepatic VLDL secretion of genetically obese Zucker rats is inhibited by a high-fat diet,”
  9. (2007). Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease,”
  10. (1995). Intracellular triacylglycerol lipase: its role in the assembly of hepatic very-low-density lipoprotein (VLDL),”
  11. (1991). K r a e g e n ,P .W .C l a r k ,A .B .J e n k i n s ,E .A .D a l e y ,D .J . Chisholm,and L.H.Storlien,“Development ofmuscleinsulin resistance after liver insulin resistance in high-fat-fed rats,”
  12. (1998). L a n k e s t e r ,A .M .B r o w n ,a n dV .A .Z a m m i t ,“ U s eo f cytosolic triacylglycerol hydrolysis products and of exogenous fatty acid for the synthesis of triacylglycerol secreted by culturedrathepatocytes,”JournalofLipidResearch,vol.39,no. 9,
  13. (2001). Lysosomal acid lipasedeficient mice: depletion of white and brown fat, severe hepatosplenomegaly, and shortened life span,”
  14. (2000). Lysosomal Pathways of Protein Degradation, Moleculat Biology Intelligence Unit,
  15. (1979). Lysosomal triacylglycerol lipase and lipolysis in isolated rat hepatocytes,”
  16. (2008). M e n s i n k ,J .P l a t ,a n dP .S c h r a u w e n ,“ D i e ta n dn o n a l c o -holic fatty liver disease,”
  17. (2004). Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease,”
  18. (1999). Morselli-Labate et al., “Association of nonalcoholic fatty liver disease with insulin resistance,”
  19. (2009). n e c h t ,C .A g u a d o ,J .C ´ arcel et al., “Intracellular protein degradation in mammalian cells: recent developments,” Cellular and Molecular Life Sciences,
  20. Prevention of hepatic steatosis and hepatic insulin resistance in mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 knockoutmice,”CellMetabolism,vol.2,no.1,pp.55–65,2005.
  21. (1995). Protein kinase C and lipid signaling for sustained cellular responses,”
  22. (2006). Reversal of diet-induced hepatic steatosis and hepatic insulin resistance
  23. (1985). S e g l e na n dA .E .S o l h e i m ,“ C o n v e r s i o no fd e n s e lysosomesintolightlysosomesduringhepatocyticautophagy,”
  24. (1969). Simple liquid-liquid partition system for isolation of labeled oleic acid from mixtures with glycerides,”
  25. (1970). Specificity and other properties of lysosomal lipase of rat liver,”
  26. (1965). Studies on theintracellular digestive processinmammalian tissueculture cells,”
  27. (1992). The lipolysis/esterification cycle of hepatic triacylglycerol. Its role in the secretion of verylow-density lipoprotein and its response to hormones and sulphonylureas,”BiochemicalJournal,vol.284,part2,pp.457– 462,
  28. (2005). The lysosome turns fifty,”