Abstract
In cholestatic liver diseases, impaired bile excretion disrupts lipid homeostasis. We investigated changes of lipid metabolism, including mitochondrial β-oxidation, in a rat model of bile duct ligation (BDL) in which chorionic plate-derived mesenchymal stem cells (CP-MSCs) were transplanted. Serum cholesterol level, which was elevated after BDL, was significantly decreased following CP-MSC transplantation. The expression levels of genes involved in intracellular lipid uptake, including long-chain fatty acyl-CoA synthetases and fatty acid transport proteins, were decreased in rats after BDL; however, they were not significantly changed by subsequent CP-MSC transplantation. Carnitine palmitoyltransferase 1A (CPT1A), a rate-limiting enzyme in mitochondrial β-oxidation, was upregulated after BDL and then was downregulated after CP-MSC transplantation. CPT1A expression was changed via microRNA-33—a posttranscriptional regulator of CPT1A—in a peroxisome proliferator-activated receptor α-independent manner. Cellular adenosine triphosphate production—an indicator of mitochondrial function—was reduced after BDL and was restored by CP-MSC transplantation. Expression levels of heme oxygenases also were significantly affected following BDL and CP-MSC transplantation. Lipid metabolism is altered in response to chronic cholestatic liver injury and can be restored by CP-MSC transplantation. Our study findings support the therapeutic potential of CP-MSCs in cholestatic liver diseases and help in understanding the fundamental mechanisms by which CP-MSCs affect energy metabolism.
Highlights
Cholestatic liver injury, which is caused by accumulation of bile acids and lipids, comprises a wide spectrum ranging from acute transient hepatitis to cirrhosis with portal hypertension [1,2,3]
We previously found that full-term placenta harbors several types of PD-Mesenchymal stem cells (MSCs), Stem Cells International including chorionic plate-derived MSCs (CP-MSCs), chorionic villus-derived MSCs, and Wharton’s jelly-derived MSCs [9]
To assess the effect of transplantation of CP-MSCs on cholestatic liver injury, bile duct ligation (BDL) rats were divided into 2 groups: rats in the transplanted group were injected with CP-MSCs, and rats in the nontransplanted group were injected with the culture medium
Summary
Cholestatic liver injury, which is caused by accumulation of bile acids and lipids, comprises a wide spectrum ranging from acute transient hepatitis to cirrhosis with portal hypertension [1,2,3]. The liver controls central processes of lipid metabolism including fatty acid synthesis, mitochondrial β-oxidation, and phospholipid transport. Impaired bile excretion, caused by biliary obstruction or liver damage, disrupts cholesterol and phospholipid metabolism [4]. Mesenchymal stem cells (MSCs) are multipotent adult stem cells that can differentiate into various cell types of the three germ layers (i.e., the ectoderm, mesoderm, and endoderm) [6]. We previously found that full-term placenta harbors several types of PD-MSCs, Stem Cells International including chorionic plate-derived MSCs (CP-MSCs), chorionic villus-derived MSCs, and Wharton’s jelly-derived MSCs [9]. CP-MSCs are highly capable of differentiating into various lineage cells, including hepatocytes. CPMSCs have been demonstrated to have anti-inflammatory, antifibrotic, and proregenerative properties in the damaged liver [10, 11]
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