Elsevier

Life Sciences

Volume 156, 1 July 2016, Pages 47-56
Life Sciences

Chenodeoxycholic acid significantly impacts the expression of miRNAs and genes involved in lipid, bile acid and drug metabolism in human hepatocytes

https://doi.org/10.1016/j.lfs.2016.04.037Get rights and content
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Abstract

Aims

Bile acids (BAs) are important gut signaling hormones, influencing lipid, glucose, and energy homeostasis. The exact mechanisms behind these effects are not yet fully understood. Lately, they have come to the fore as putative therapeutics in metabolic diseases, such as e.g. nonalcoholic fatty liver disease (NAFLD). We elucidate to what extent BAs impacts on the mRNAome and microRNAome in hepatocytes to gather novel insights into the mechanisms behind metabolic and toxicologic effects of bile acids.

Main methods

Five batches of primary human hepatocytes were treated with 50 μmol/l chenodeoxycholic acid (CDCA) for 24 or 48 h. Total RNA was extracted, size fractionated and subjected to Next Generation Sequencing to generate mRNA and miRNA profiles.

Key findings

Expression of 738 genes and 52 miRNAs were CDCA dependently decreased, whereas 1566 genes and 29 miRNAs were significantly increased in hepatocytes. Distinct gene clusters controlling BA and lipid homeostasis (FGF(R), APO and FABP family members, HMGCS2) and drug metabolism (CYP, UGT and SULT family members) were significantly modulated by CDCA. Importantly, CDCA affected distinct microRNAs, including miR-34a, -505, -885, -1260 and -552 that systematically correlated in expression with gene clusters responsible for bile acid, lipid and drug homeostasis incorporating genes, such as e.g. SLCO1B1, SLC22A7, FGF19, CYP2E1, CYP1A2, APO family members and FOXO3.

Significance

Bile acids significantly modulate metabolic and drug associated gene networks that are connected to distinct shifts in the microRNAome These findings give novel insights on how BA enfold metabolic and system toxic effects.

Abbreviations

ABC
ATP-binding cassette transporter
AGPAT2
1-acylglycerol-3-phosphate O-acyltransferase
AhR
arylhydrocarbon receptor
AKR1C1
aldo-keto reductase 1C1
APO
apolipoprotein
ASBT
apical sodium dependent bile acid transporter
BAs
bile acids
BSEP
bile salt export pump
CDCA
chenodeoxycholic acid
CPT1A
carnitine palmitoyltransferase 1A
CYP
cytochrome P450
DM
drug metabolism
DMSO
dimethyl sulfoxide
FABP
fatty acid-binding protein
FASN
fatty acid synthase gene
FDR
false discovery rate
FXR
farnesoid X receptor
HMGCS2
3-hydroxy-3-methylglutaryl-CoA synthase 2
LDLR
low density lipoprotein receptor
mRNA
messenger RNA
miRNA
microRNA
NAFLD
nonalcoholic fatty liver disease
NASH
nonalcoholic steatohepatitis
NPC1L1
Niemann-Pick C1-like 1 gene
NTCP
Na+-taurocholate cotransporting polypeptide
OATP
organic anion transport protein
OST
organic solute transporter
PCR
polymerase chain reaction
PHHs
primary human hepatocytes
PPAR-γ
peroxisome proliferator-activated receptor
RT-PCR
real-time PCR
S1PR
sphingosine-1-phosphate receptor
SHP
small heterodimer partner
SLC
solute carrier family
STARD3
StAR-related lipid transfer domain protein 3
SULT
sulfotransferase
UGT
UDP-glucuronosyltransferase
UTR
untranslated region

Keywords

Bile acids
Chenodeoxycholic acid
Primary human hepatocytes
mRNA profiling
microRNA profiling
microRNA-34a

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