Abstract
Intrahepatic cholestasis induced by drug toxicity, bile salt export pump (BSEP) deficiency, or pregnancy frequently causes cholestatic liver damage, which ultimately may lead to liver fibrosis and cirrhosis. Here, the preventive and therapeutic effects of peroxisome proliferator-activated receptor α (PPARα) signaling activated by fenofibrate was evaluated on cholestatic liver damage. Metabolomic analysis revealed that alpha-naphthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis resulted in the accumulation of serum long-chain acylcarnitines and triglyceride, and the reduced expression of four fatty acid β-oxidation (β-FAO) relevant genes (Cpt1b, Cpt2, Mcad and Hadha), indicating the disruption of β-FAO. The increase of acylcarnitines in hepatic cell resulted in the enhanced expression of anti-oxidative genes glutathione S-transferases (Gsta2 and Gstm3) directly. As direct PPARα-regulated genes, Cpt1b, Cpt2, and Mcad were up-regulated after pretreatment with PPARα agonist, fenofibrate, indicating the improvement of β-FAO. In the end, the disrupted bile acid metabolism in the enterohepatic circulation and the enhanced oxidative stress and inflammation cytokines induced by ANIT exposure were significantly recovered with the improvement of β-FAO using fenofibrate treatment. These findings provide the rationale for the use of PPARα agonists as therapeutic alternatives for cholestatic liver damage.
Highlights
Intrahepatic cholestasis induced by drug toxicity, bile salt export pump (BSEP) deficiency, or pregnancy frequently causes cholestatic liver damage, which may lead to liver fibrosis and cirrhosis
Biochemical analysis found that alpha-naphthyl isothiocyanate (ANIT) exposure dramatically increased serum aspartate transferase (AST) and alanine transferase (ALT) (P < 0.001), as well as serum alkaline phosphatase (ALP) (P < 0.001) that is an intrahepatic cholestasis marker (Fig. 1a), indicating a severe cholestasis induced by ANIT
Four mitochondrial β-FAO relevant genes, medium-chain acyl-CoA dehydrogenase (Mcad) which catalyzes the first step of FAO10, carnitine palmitoyltransferase (Cpt1b and Cpt2) which transports fatty acids across the mitochondrial membrane[10], and hydroxyacyl-CoA dehydrogenase (Hadha) which catalyzes the final 3 steps in β-FAO, were significantly down-regulated (P < 0.01) in ANIT group (Fig. 1d)
Summary
Intrahepatic cholestasis induced by drug toxicity, bile salt export pump (BSEP) deficiency, or pregnancy frequently causes cholestatic liver damage, which may lead to liver fibrosis and cirrhosis. The disrupted bile acid metabolism in the enterohepatic circulation and the enhanced oxidative stress and inflammation cytokines induced by ANIT exposure were significantly recovered with the improvement of β-FAO using fenofibrate treatment. These findings provide the rationale for the use of PPARα agonists as therapeutic alternatives for cholestatic liver damage. The present study revealed that PPARα signaling activated by fenofibrate could improve mitochondrial β-FAO and recover the disorder of bile acid metabolism, and decrease the oxidative www.nature.com/scientificreports/. Stress and inflammation cytokines in alpha-naphthyl isothiocyanate (ANIT)-induced cholestasis, suggesting the potential use of PPARα agonists as therapeutic alternatives for cholestatic liver damage
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