Background/Aims Disrupted bile acid regulation and accumulation in the liver can contribute to progressive liver damage and fibrosis. However, the effects of bile acids on the activation of hepatic stellate cells (HSCs) remain unclear. This study investigated the effects of bile acids on HSC activation during liver fibrosis, and examined the underlying mechanisms.
Methods The immortalized HSCs, LX-2 and JS-1cells were used for the in vitro study. in vitro, the adeno-associated viruses adeno-associated virus-sh-S1PR2 and JTE-013 were used to pharmacologically inhibit the activity of S1PR2 in a murine model of fibrosis induced by a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Histological and biochemical analyses were performed to study the involvement of S1PR2 in the regulation of fibrogenic factors as well as the activation properties of HSCs.
Results S1PR2 was the predominant S1PR expressed in HSCs and was upregulated during taurocholic acid (TCA) stimulation and in cholestatic liver fibrosis mice. TCA-induced HSC proliferation, migration and contraction and extracellular matrix protein secretion were inhibited by JTE-013 and a specific shRNA targeting S1PR2 in LX-2 and JS-1 cells. Meanwhile, treatment with JTE-013 or S1PR2 deficiency significantly attenuated liver histopathological injury, collagen accumulation, and the expression of fibrogenesis-associated genes in mice fed a DDC diet. Furthermore, TCAmediated activation of HSCs through S1PR2 was closely related to the yes-associated protein (YAP) signaling pathway via p38 mitogen-activated protein kinase (p38 MAPK).
Conclusions TCA-induced activation of the S1PR2/p38 MAPK/YAP signaling pathways plays a vital role in regulating HSC activation, which might be therapeutically relevant for targeting cholestatic liver fibrosis.
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Background/Aims In order to elucidate the possible mechanism of increase of y -glutamyl transpeptidase (y-GTP) activity in cholestatic liver and serum was studied. Method: Rats were divided into eight groups: Normal, sham operated control, bile duct obstruction (BDO) alone (BDO group), BDO plus taurocholic acid (TCA) injection (BDO plus TCA group), BDO plus tauroursodeoxycholic acid (TUDCA) injection (BDO plus TUDCA group), choledoco-caval shunt (CCS) operation (CCS groups), CCS plus TCA injection (CCS plus TCA group), and CCS plus TUDCA injection (CCS plus TUDCA group). Y -GTP activity was determined in the serum and liver cytosolic, mitochondrial and microsomal preparations isolated from above experimental rats. The values of Km and Vmax in this hepatic enzyme was measured. Result: the activities of liver cytosolic and microsomal y -GTP showed a significant increase in the CCS group. The activities of liver cytosolic, mitochondrial and microsomal y -GTP showed a significant increase in the BDO group. And the activity of serum y -GTP showed a marked increase in teth CCS and BDO poups. However, y-GTP activities in the serum and in liver microsomal prepatation rose more rapidly in the BDO group tban CCS. Y -GTP activity in liver cytosolic and microsomal preparatians, and its Vmax value incmmxl significantly in both CCS plus TCA group, and BDO plus TCA group than each control group, such as CCS and BDO group. On the other hand, the values of Km of the hepatic subcellular y -GTP did not change in the all experimental groups. Sennn y -GTP activity increased significantly in both CCS plus 7CA group, and BDO plus TCA group than each control group. However, these serum and hepatic enzyme activities did not change in both CCS plus TUDCA group and BDO plus TUDCA group. Conclusions: The above results suggest that 7CA stimulates biosynthesis of the y-GTP in the liver. And the elevations of the serum enzymes activity thought to be caused by increase of hepatocyte membrane permeability by a physical property (detergency) of TCA, which cause the enzyme to leak into the blood in large quantities. (Korean J Hepatol 1997;6:210 226)
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