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

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• 作者：Regina Krattinger^a ; Adrian Boströ ; m^b ; Serene M.L. Lee^c ; Wolfgang E. Thasler^c ; Helgi B. Schiö ; th^b ; Gerd A. Kullak-Ublick^a ; ^{gerd.kullak@usz.ch" class="auth_mail" title="E-mail the corresponding author} ; Jessica Mwinyi^a ; ^b
• 关键词：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 discov
• 刊名：Life Sciences
• 出版年：2016
• 出版时间：1 July 2016
• 年：2016
• 卷：156
• 期：Complete
• 页码：47-56
• 全文大小：2568 K

文摘

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.