Nonalcoholic fatty liver disease (
NAFLD) is one of the most frequent causes of abnormal
liver dysfunction, and its prevalence has markedly increased. We previously evaluated the expression of
fatty acid metabolism-related genes in
NAFLD and reported changes in expression that could contribute to increased
fatty acid synthesis. In the present study, we evaluated the expression of additional
fatty acid metabolism-related genes in larger groups of
NAFLD (n=26) and normal liver (n=10) samples. The target genes for real-time PCR analysis were as follows:
acetyl-CoA carboxylase (ACC) 1, ACC2,
fatty acid synthase (FAS),
sterol regulatory element-binding protein 1c (SREBP-1c), and
adipose differentiation-related protein (ADRP) for evaluation of de novo synthesis and uptake of
fatty acids;
carnitine palmitoyltransferase 1a; (CPT1a),
long-chain acyl-CoA dehydrogenase (LCAD), long-chain L-3-hydroxyacylcoenzyme A
dehydrogenase alpha (HADHalpha),
uncoupling protein 2 (UCP2), straight-chain
acyl-CoA oxidase (ACOX),
branched-chain acyl-CoA oxidase (BOX),
cytochrome P450 2E1 (
CYP2E1), CYP4A11, and
peroxisome proliferator-activated receptor (
PPAR)alpha for oxidation in the mitochondria, peroxisomes and microsomes;
superoxide dismutase (SOD),
catalase, and
glutathione synthetase (GSS) for
antioxidant pathways; and
diacylglycerol O-acyltransferase 1 (DGAT1),
PPARgamma, and
hormone-sensitive lipase (HSL) for
triglyceride synthesis and catalysis. In
NAFLD, although
fatty acids accumulated in hepatocytes, their de novo synthesis and uptake were up-regulated in association with increased expression of ACC1, FAS,
SREBP-1c, and ADRP.
Fatty acid oxidation-related genes, LCAD, HADHalpha, UCP2, ACOX, BOX,
CYP2E1, and CYP4A11, were all overexpressed, indicating that oxidation was enhanced in
NAFLD, whereas the expression of CTP1a and
PPARalpha was decreased. Furthermore, SOD and
catalase were also overexpressed, indicating that
antioxidant pathways are activated to neutralize
reactive oxygen species (ROS), which are overproduced during oxidative processes. The expression of DGAT1 was up-regulated without increased
PPARgamma expression, whereas the expression of HSL was decreased. Our data indicated the following regarding
NAFLD: i) increased de novo synthesis and uptake of
fatty acids lead to further
fatty acid accumulation in hepatocytes; ii) mitochondrial
fatty acid oxidation is decreased or fully activated; iii) in order to
complement the function of mitochondria (beta-oxidation), peroxisomal (beta-oxidation) and microsomal (omega-oxidation) oxidation is up-regulated to decrease
fatty acid accumulation; iv)
antioxidant pathways including SOD and
catalase are enhanced to neutralize ROS overproduced during mitochondrial, peroxisomal, and microsomal oxidation; and v) lipid droplet formation is enhanced due to increased DGAT expression and decreased HSL expression. Further studies will be needed to clarify how
fatty acid synthesis is increased by
SREBP-1c, which is under the control of
insulin and
AMP-activated protein kinase.