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.
Highlights
Apolipoprotein A-I is a single polypeptide of 243 amino acids with a molecular mass of 28.1 kDa, mainly present in plasma as a component of highdensity lipoprotein (HDL) [1]
Derived Apolipoprotein A-I (apoA-I) enters the circulation associated with chylomicrons and it is rapidly transferred to HDL during conversion of chylomicrons into chylomicron remnants by lipoprotein lipase [2,3], and hepatic apoA-I is secreted in the circulation in a lipid-free, or minimally lipidated form [2,4]
Statistical analysis following histomorphometric evaluation of the hematoxylin and eosin (H&E) sections revealed that the number of lipid droplets within hepatocytes was significantly elevated in the apoA-I –/– mice than in the C57BL/6 mice (P = 0.0001) (Figures 1A, B, E, F)
Summary
Apolipoprotein A-I (apoA-I) is a single polypeptide of 243 amino acids with a molecular mass of 28.1 kDa, mainly present in plasma as a component of highdensity lipoprotein (HDL) [1]. ApoA-I is expressed primarily by the intestine and the liver, other tissues express it. Derived apoA-I enters the circulation associated with chylomicrons and it is rapidly transferred to HDL during conversion of chylomicrons into chylomicron remnants by lipoprotein lipase [2,3], and hepatic apoA-I is secreted in the circulation in a lipid-free, or minimally lipidated form [2,4]. Lipid-free or minimally lipidated apoA-I plays an important role in the de novo biogenesis of HDL [1]. In the early steps of this pathway, apoA-I acquires phospholipids and cholesterol via its interactions with the ATP-binding cassette A1 (ABCA1). Through a series of intermediate steps that are currently poorly understood, apoA-I is gradually lipi-
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