Apolipoprotein A-I Modulates Processes Associated with Diet-Induced Nonalcoholic Fatty Liver Disease in Mice
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.
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.
- 1.Zannis VI, Kypreos KE, Chroni A, Kardassis D, Zanni EE. (2004) Lipoproteins and atherogenesis. In: Molecular Mechanisms of Atherosclerosis. Loscalzo J (ed). Taylor & Francis, New York, NY, pp. 111–74.Google Scholar
- 2.Herbert PN, Assmann G, Gotto AM Jr, Fredrickson DS. (1982) Familial lipoprotein deficiency: alpha beta lipoproteinemia, hypobetalipoproteinemia, and Tangier disease. In: The Metabolic Basis of Inherited Disease. Stanbury JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, and Brown MS (eds.). McGraw-Hill, New York, pp. 589–651.Google Scholar
- 15.Franceschini G, Sirtori CR, Capurso A, Weisgraber KH, Mahley RW. (1980) A-IMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family. J. Clin. Invest. 66:892–900.CrossRefGoogle Scholar
- 22.Kypreos KE, Van Dijk KW, Havekes LM, Zannis VI. (2005) Generation of a recombinant apolipoprotein E variant with improved biological functions: hydrophobic residues (LEU-261, TRP-264, PHE-265, LEU-268, VAL-269) of apoE can account for the apoE-induced hypertriglyceridemia. J. Biol. Chem. 280:6276–84.CrossRefGoogle Scholar
- 23.Chroni A, et al. (2004) Substitutions of glutamate 110 and 111 in the middle helix 4 of human apolipoprotein A-I (apoA-I) by alanine affect the structure and in vitro functions of apoA-I and induce severe hypertriglyceridemia in apoA-I-deficient mice. Biochemistry. 43:10442–57.CrossRefGoogle Scholar
- 28.Karavia EA, Papachristou DJ, Kotsikogianni I, Triantafyllidou IE, Kypreos KE. (2012) Lecithin/cholesterol acyltransferase modulates diet-induced hepatic deposition of triglycerides in mice. J. Nutr. Biochem. 2012, Jul 23 [Epub ahead of print].Google Scholar
- 30.Kypreos KE, Van Dijk KW, van Der Zee A, Havekes LM, Zannis VI. (2001) Domains of apolipoprotein E contributing to triglyceride and cholesterol homeostasis in vivo. Carboxylterminal region 203–299 promotes hepatic very low density lipoprotein-triglyceride secretion. J. Biol. Chem. 276:19778–86.CrossRefGoogle Scholar
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