Apolipoprotein A-I modulates processes associated with diet-induced nonalcoholic fatty liver disease in mice

Mol Med. 2012 Sep 7;18(1):901-12. doi: 10.2119/molmed.2012.00113.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Adiposity / drug effects
  • Animals
  • Apolipoprotein A-I / deficiency
  • Apolipoprotein A-I / metabolism*
  • Body Weight / drug effects
  • Calorimetry
  • Diet*
  • Fatty Liver / blood
  • Fatty Liver / genetics
  • Fatty Liver / metabolism*
  • Fatty Liver / pathology*
  • Feeding Behavior
  • Gene Expression Regulation / drug effects
  • Glucose Intolerance / complications
  • Glucose Intolerance / genetics
  • Glucose Intolerance / pathology
  • Insulin / pharmacology
  • Intestinal Mucosa / metabolism
  • Intestines / drug effects
  • Intestines / pathology
  • Kinetics
  • Lipogenesis / drug effects
  • Lipogenesis / genetics
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease
  • Postprandial Period / drug effects
  • Recombination, Genetic / drug effects
  • Recombination, Genetic / genetics
  • Triglycerides / blood
  • Triglycerides / metabolism


  • Apolipoprotein A-I
  • Insulin
  • Triglycerides