Effect of HFD/STZ on expression of genes involved in lipid, cholesterol and glucose metabolism in rats.
OBJECTIVE
The aim of the study was to evaluate lipid, cholesterol and glucose metabolism in a novel rat model of non-alcoholic fatty liver disease (NAFLD).


METHODS
Rats (Wistar) were fed high fat/cholesterol diet (HFD) and a single low dose (35mg/kg) of streptozotocin (STZ). Collagen and glycogen content, oxidative stress and glucokinase activity were measured using biochemical assays. Other metabolic pathways were assessed by qRT-PCR.


RESULTS
HFD/STZ treated rats, compared to control ones, showed an increase in expression of biomarkers of inflammation (TNFα, IL6), fibrosis (TGFβ), mitochondrial stress (UCP2) and oxidative stress (GSH and carbonylated proteins) but not of ER stress (CHOP, XBP1). Additionally, HFD/STZ treatment caused a reduction in glycogen content, glucokinase activity (a limiting step in glycolysis) and expression of ChREBP gene (a de novo lipogenesis regulator), suggesting a modified glycolytic pathway. The cholesterol biosynthesis in HFD/STZ treated rats was inhibited (reduced expression of SREBP-2-regulated HMGCoA red and LDLr), instead the cholesterol catabolism was increased, as shown by the mRNA induction of the CYP7A1 and CYP8B1 (key genes for BA acid). A reduced gene expression of FXR-dependent SHP (a key gene for feedback inhibition of CYP7A1 and CYP8B1) and of bile acids (NTCP, OATP1A1, BSEP) and cholesterol (ABCA1) transporters was found.


CONCLUSIONS
These results widely extend the characterization of HFD/STZ rat model, which might mimic the NAFLD/NASH in diabetic humans.
Istituto di Biologia e Biotecnologia Agraria, CNR, Via Moruzzi 1, 56124 Pisa, Italy.
Luisa
L
Pozzo
Istituto di Biologia e Biotecnologia Agraria, CNR, Via Moruzzi 1, 56124 Pisa, Italy.
Andrea
A
Vornoli
Istituto di Biologia e Biotecnologia Agraria, CNR, Via Moruzzi 1, 56124 Pisa, Italy.
Ilaria
I
Coppola
Istituto di Biologia e Biotecnologia Agraria, CNR, Via Moruzzi 1, 56124 Pisa, Italy.
Clara Maria Della
CM
Croce
Istituto di Biologia e Biotecnologia Agraria, CNR, Via Moruzzi 1, 56124 Pisa, Italy.
Lucia
L
Giorgetti
Istituto di Biologia e Biotecnologia Agraria, CNR, Via Moruzzi 1, 56124 Pisa, Italy.
Pier Giovanni
PG
Gervasi
Istituto di Biologia e Biotecnologia Agraria, CNR, Via Moruzzi 1, 56124 Pisa, Italy. Electronic address: v.longo@ibba.cnr.it.
Vincenzo
V
Longo
D000818:Animals; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D005786:Gene Expression Regulation; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D017208:Rats, Wistar; D013311:Streptozocin
D013311:Streptozocin; D006003:Glycogen; D002784:Cholesterol; D005947:Glucose
Bile acid transporters; Cholesterol and glucose metabolism; HFD/STZ rat model; Inflammation; Lipid; Mitochondrial and endoplasmic reticulum oxidative stress