Rosiglitazone alleviates intrahepatic cholestasis induced by α‐naphthylisothiocyanate in mice: The role of circulating 15‐deoxy‐Δ^12,14‐PGJ₂ and Nogo

Abstract

Background and Purpose Intrahepatic cholestasis is mainly caused by dysfunction of bile secretion and has limited effective treatment. Rosiglitazone is a synthetic agonist of PPARγ, whose endogenous agonist is 15‐deoxy‐Δ12,14‐PGJ2 (15d‐PGJ2). Reticulon 4B (Nogo‐B) is the detectable Nogo protein family member in the liver and secreted into circulation. Here, we determined if rosiglitazone can alleviate intrahepatic cholestasis in mice. Experimental Approach Wild‐type, hepatocyte‐specific PPARγ or Nogo‐B knockout mice received intragastric administration of α‐naphthylisothiocyanate (ANIT) and/or rosiglitazone, followed by determination of intrahepatic cholestasis and the involved mechanisms. Serum samples from primary biliary cholangitis (PBC) patients and non‐PBC controls were analysed for cholestasis‐related parameters. Key Results Rosiglitazone prevented wild type, but not hepatocyte‐specific PPARγ deficient mice from developing ANIT‐induced intrahepatic cholestasis by increasing expression of bile homeostatic proteins, reducing hepatic necrosis, and correcting abnormal serum parameters and enterohepatic circulation of bile. Nogo‐B knockout provided protection similar to that of rosiglitazone treatment. ANIT‐induced intrahepatic cholestasis decreased 15d‐PGJ2 but increased Nogo‐B in serum, and both were corrected by rosiglitazone. Nogo‐B deficiency in the liver increased 15d‐PGJ2 production, thereby activating expression of PPARγ and bile homeostatic proteins. Rosiglitazone and Nogo‐B deficiency also alleviated cholestasis‐associated dyslipidemia. In addition, rosiglitazone reduced symptoms of established intrahepatic cholestasis in mice. In serum from PBC patients, the decreased 15d‐PGJ2 and increased Nogo‐B levels were significantly correlated with classical cholestatic markers. Conclusions and Implications Levels of 15d‐PGJ2 and Nogo are important biomarkers for intrahepatic cholestasis. Synthetic agonists of PPARγ could be used for treatment of intrahepatic cholestasis and cholestasis‐associated dyslipidemia.

Tectorigenin alleviates intrahepatic cholestasis by inhibiting hepatic inflammation and bile accumulation via activation of PPARγ

“…Consistent with previous studies (Zhang et al, 2020), ANIT treatment alone resulted in the accumulation of bile acids in the liver and serum of mice, and reduced bile acid contents in the faeces, which suggested that bile flow was mainly obstructed from the liver to the intestine (Figure 3a). CLD in mice was associated with reduced hepatic gene expression of canalicular transporters of bile salts (BSEP encoded by Abcb11 ), bilirubin (ABCC2, encoded by Abcc2 ), and phytosterols (ABCG5 and ABCG8, encoded by Abcg5 and Abcg8 )(El Kasmi et al, 2018; Yang et al, 2019; Zhang et al, 2020). Consistent with biochemical cholestasis, mRNA expression of export transporters ( Abcc2 and Bsep ), phytosterol transporters ( Abcg5 and Abcg8 ), and uptake transporters ( Ntcp and Oatp1 ) were significantly suppressed in mice with ANIT‐induced CLD (Figure 3b).…”

“…At 2 weeks after infection, the mice were used for experiments, as described above. Extraction and determination of total bile acids (TBA) in mouse liver and intestine was performed as previously reported (Zhang et al, 2020).…”

Tectorigenin alleviates intrahepatic cholestasis by inhibiting hepatic inflammation and bile accumulation via activation of PPARg

“…TEC rescued bile metabolic dysfunction in mice with intrahepatic cholestasis induced by ANIT or DDC We then undertook experiments to verify bile metabolism after TEC intervention in the CLD experimental model. Consistent with previous studies [29] , ANIT treatment alone resulted in the accumulation of bile acids in the liver and serum of mice, and reduced the content of bile acids in feces, which suggested that bile flow was mainly obstructed from the liver to the intestine (Figure 3A). CLD in mice was associated with reduced hepatic gene expression of canalicular transporters of bile salts (Bsep encoded by Abcb11), bilirubin (Mrp2, encoded by Abcc2), and phytosterols (the heterodimer sterolin1 and sterolin2, encoded by ABCG5 and ABCG8) [20,29,30] .…”

“…Consistent with previous studies [29] , ANIT treatment alone resulted in the accumulation of bile acids in the liver and serum of mice, and reduced the content of bile acids in feces, which suggested that bile flow was mainly obstructed from the liver to the intestine (Figure 3A). CLD in mice was associated with reduced hepatic gene expression of canalicular transporters of bile salts (Bsep encoded by Abcb11), bilirubin (Mrp2, encoded by Abcc2), and phytosterols (the heterodimer sterolin1 and sterolin2, encoded by ABCG5 and ABCG8) [20,29,30] . Concomitant with biochemical cholestasis, mRNA expression of export transporters (Mrp2 and Bsep), phytosterol transporters (ABCG5 and ABCG8) and uptake transporters (Ntcp, Oatp) were significantly suppressed in mice with ANIT-induced CLD (Figure 3B).…”

“…In addition, PPARγ inhibits the transcriptional activation of inflammatory response genes and represses cellular toll-like receptor signaling in inflammatory cells as well as in cholangiocytes [39] . Importantly, recent studies have shown that rosiglitazone improve intrahepatic cholestasis and cholestasis-associated dyslipidemia induced by ANIT [29] . These data indicated that PPARγ activation may be an effective strategy for the treatment of CLD, especially for the improvement of liver fibrosis and inflammation, thereby limiting disease progression.…”