title: Apolipoprotein A-I modulates processes associated with diet-induced nonalcoholic fatty liver disease in mice.
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) [corrected], 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-I(Milano) 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.
authors.affiliation: Pharmacology Laboratory, Department of Medicine, University of Patras Medical School, Rio, Greece.
authors.forename: Eleni A
authors.initials: EA
authors.lastname: Karavia
authors.forename: Dionysios J
authors.initials: DJ
authors.lastname: Papachristou
authors.forename: Kassiani
authors.initials: K
authors.lastname: Liopeta
authors.forename: Irene-Eva
authors.initials: IE
authors.lastname: Triantaphyllidou
authors.forename: Odyssefs
authors.initials: O
authors.lastname: Dimitrakopoulos
authors.forename: Kyriakos E
authors.initials: KE
authors.lastname: Kypreos
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D016632:Apolipoprotein A-I / Q000172:deficiency / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D002151:Calorimetry; D004032:Diet; D005234:Fatty Liver / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005247:Feeding Behavior; D005786:Gene Expression Regulation / Q000187:drug effects; D018149:Glucose Intolerance / Q000150:complications / Q000235:genetics / Q000473:pathology; D007328:Insulin / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D007700:Kinetics; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D019518:Postprandial Period / Q000187:drug effects; D011995:Recombination, Genetic / Q000187:drug effects / Q000235:genetics; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
chemical_list: D016632:Apolipoprotein A-I; D007328:Insulin; D014280:Triglycerides