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Molecular Medicine

, Volume 18, Issue 6, pp 901–912 | Cite as

Apolipoprotein A-I Modulates Processes Associated with Diet-Induced Nonalcoholic Fatty Liver Disease in Mice

  • Eleni A Karavia
  • Dionysios J Papachristou
  • Kassiani Liopeta
  • Irene-Eva Triantaphyllidou
  • Odyssefs Dimitrakopoulos
  • Kyriakos E. Kypreos
Research Article

Abstract

Apolipoprotein A-I (apoA-I) is the main protein of high-density lipoprotein (HDL). We investigated the involvement of apoA-I in diet-induced accumulation of triglycerides in hepatocytes and its potential role in the treatment of nonalcoholic fatty liver disease (NAFLD). ApoA-I-deficient (apoA-I−/−) mice showed increased diet-induced hepatic triglyceride deposition and disturbed hepatic histology while they exhibited reduced glucose tolerance and insulin sensitivity. Quantification of FASN (fatty acid synthase 1), DGAT-1 (diacylglycerol O-acyltransferase 1), and PPARγ (peroxisome proliferator-activated receptor γ) mRNA expression suggested that the increased hepatic triglyceride content of the apoA-I−/− mice was not due to de novo synthesis of triglycerides. Similarly, metabolic profiling did not reveal differences in the energy expenditure between the two mouse groups. However, apoA-I−/− mice exhibited enhanced intestinal absorption of dietary triglycerides (3.6 ± 0.5 mg/dL/min for apoA-I−/− versus 2.0 ± 0.7 mg/dL/min for C57BL/6 mice, P < 0.05), accelerated clearance of postprandial triglycerides and a reduced rate of hepatic very low density lipoprotein (VLDL) triglyceride secretion (9.8 ± 1.1 mg/dL/min for apoA-I−/− versus 12.5 ± 1.3 mg/dL/min for C57BL/6 mice, P < 0.05). In agreement with these findings, adenovirus-mediated gene transfer of apoA-IMilano in apoA-I−/− mice fed a Western-type diet for 12 wks resulted in a significant reduction in hepatic triglyceride content and an improvement of hepatic histology and architecture. Our data extend the current knowledge on the functions of apoA-I, indicating that in addition to its well-established properties in atheroprotection, it is also an important modulator of processes associated with diet-induced hepatic lipid deposition and NAFLD development in mice. Our findings raise the interesting possibility that expression of therapeutic forms of apoA-I by gene therapy approaches may have a beneficial effect on NAFLD.

Notes

Acknowledgments

This work was supported by the European Community’s Seventh Framework Programme [FP7/2007–2013] grant agreements PIRG02-GA-2007-219129 and PIRG02-GA-2009-256402, and the University of Patras Karatheodoris research grants C566 and D155. This work was part of the activities of the intramural research network MetSNet of the University of Patras.

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Authors and Affiliations

  • Eleni A Karavia
    • 1
  • Dionysios J Papachristou
    • 2
  • Kassiani Liopeta
    • 3
  • Irene-Eva Triantaphyllidou
    • 2
  • Odyssefs Dimitrakopoulos
    • 3
  • Kyriakos E. Kypreos
    • 1
  1. 1.Pharmacology Laboratory, Department of MedicineUniversity of Patras Medical School, PanepistimioupolisRioGreece
  2. 2.Anatomy, Histology and Embryology Laboratory, Department of MedicineUniversity of Patras Medical SchoolRioGreece
  3. 3.Microbiology Clinic, Department of MedicineUniversity of Patras Medical SchoolRioGreece

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