Elsevier

Journal of Hepatology

Volume 62, Issue 3, March 2015, Pages 720-733
Journal of Hepatology

Review
Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease

https://doi.org/10.1016/j.jhep.2014.10.039Get rights and content
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open access

Summary

Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor belonging, together with PPARγ and PPARβ/δ, to the NR1C nuclear receptor subfamily. Many PPARα target genes are involved in fatty acid metabolism in tissues with high oxidative rates such as muscle, heart and liver. PPARα activation, in combination with PPARβ/δ agonism, improves steatosis, inflammation and fibrosis in pre-clinical models of non-alcoholic fatty liver disease, identifying a new potential therapeutic area. In this review, we discuss the transcriptional activation and repression mechanisms by PPARα, the spectrum of target genes and chromatin-binding maps from recent genome-wide studies, paying particular attention to PPARα-regulation of hepatic fatty acid and plasma lipoprotein metabolism during nutritional transition, and of the inflammatory response. The role of PPARα, together with other PPARs, in non-alcoholic steatohepatitis will be discussed in light of available pre-clinical and clinical data.

Abbreviations

PPAR
peroxisome proliferator-activated receptor
FAO
fatty acid oxidation
FA
fatty acid
APR
acute phase response
NASH
non-alcoholic steatohepatitis
NAFLD
non-alcoholic fatty liver disease
CVD
cardiovascular disease
LDL
low density lipoprotein
HDL-C
high density lipoprotein cholesterol
SPPARM
selective PPAR modulator
AF-1
activation function-1
MAPK
mitogen-activated protein kinase
DBD
DNA binding domain
PPRE
PPAR response element
DR-1
direct repeat-1
RXR
retinoid X receptor
LBD
ligand binding domain
NCoR
nuclear receptor co-repressor
PKC
protein kinase C
SUMO
small ubiquitin-like modifier
AF-2
activation function-2
LBP
ligand binding pocket
CBP
CREB-binding protein
SRC-1
steroid receptor coactivator-1
ACOX1
acyl-CoA oxidase 1
LTB4
leukotriene B4
8(S)-HETE
8(S)-hydroxyeicosatetraenoic acid
8-LOX
8-lipoxygenase
FATP-1
fatty acid transport protein-1
FAS
fatty acid synthase
16:0/18:1-GPC
1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine
ATGL
adipose triglyceride lipase
TG
triglyceride
HSL
hormone-sensitive lipase
EC50
half maximal effective concentration
GAL4
galactosidase 4
HAT
histone acetyltransferase
PBP
PPARα-binding protein
MED-1
mediator subunit 1
PPARαDISS
PPARα mutant with selective transrepression activity
LXR
liver X receptor
DR-4
direct repeat-4
C/EBPα
CCAAT-enhancer-binding protein alpha
TBP
TATA-binding protein
GO
gene ontology
IL-6
interleukin-6
AP-1
activator protein 1
NFκB
nuclear factor kappa-light-chain-enhancer of activated B cells
JNK
c-Jun N-terminal protein kinase
GR
glucocorticoid receptor
Fib
fibrinogen
SAA
serum amyloid A
Hg
haptoglobin
CRP
C reactive protein
STAT3
signal transducer and activator of transcription 3
Fib-β
fibrinogen-beta
GRIP-1/TIF-1
GR-interactin protein-1/transcription intermediary factor-2
ERR
estrogen-related receptor
SIRT-1
sirtuin-1
ERRE
ERR response element
LPS
lipopolysaccharide
TNF
tumor necrosis factor
ATP
adenosine triphosphate
LCFA
long-chain fatty acid
VCFA
very long-chain fatty acid
FAT/CD36
fatty acid translocase
L-FABP
liver fatty acid-binding protein
EHHADH
L-bifunctional enzyme
CPT
carnitine palmitoyltransferase
MCAD
medium-chain acyl-CoA dehydrogenase
LCAD
long-chain acyl-CoA dehydrogenase
VLCAD
very long-chain acyl-CoA dehydrogenase
let-7c
let-7 microRNA precursor
miRNA
microRNA
APO-AI
apolipoprotein-AI
HMGCS
mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase
KD
ketogenic diet
FGF21
fibroblast growth factor 21
BDH
beta-D-hydroxybutyrate dehydrogenase
LPL
lipoprotein lipase
APO-CIII
apolipoprotein-CIII
ChREBP
carbohydrate-responsive element-binding protein
HNF-4
hepatocyte nuclear factor 4
FOXO1
forkhead box O1
APO-AII
apolipoprotein-AII
ChIP-seq
chromatin immunoprecipitation-sequencing
APO-AV
apolipoprotein-AV
SNP
single-nucleotide polymorphism
SREBP-1c
sterol regulatory element binding protein-1c
Acc1
acetyl-CoA carboxylase 1
Scd-1
stearoyl-CoA desaturase-1
PKA
protein kinase A
cAMP
cyclic adenosine monophosphate
mTORC1
mammalian target of rapamycin complex 1
PI3K
phosphoinositide 3-kinase
S6K2
protein S6 kinase 2
IR
insulin resistance
AMPK
5′-AMP-activated protein kinase
T2DM
type 2 diabetes mellitus
ICAM-1
intracellular adhesion molecule-1
VCAM-1
vascular cell adhesion molecule-1
IL-1RA
interleukin-1 receptor antagonist
IκB
nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor
MetS
metabolic syndrome
MCDD
methionine choline-deficient diet
CYP4A
cytochrome P450 4A
VNN1
vanin-1
ALMS1
Alstrom syndrome 1
HFD
high-fat diet
ALT
alanine aminotransferase
APO-E2
apolipoprotein-E2
ROS
reactive oxygen species
TGFβ
transforming growth factor beta
COX-1
cyclooxygenase-1
AST
aspartate aminotransferase
γGT
gamma-glutamyl transpeptidase
LDLR
LDL-receptor
ALP
alkaline phosphatase
PUFA
polyunsaturated fatty acid

Keywords

PPARα
Fatty acid oxidation
Inflammation
Transrepression
Liver
Steatosis
NAFLD
NASH
Fibrosis

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