JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma

Abstract

Metabolic stress causes activation of the cJun NH2-terminal kinase (JNK) signal transduction pathway. It is established that one consequence of JNK activation is the development of insulin resistance and hepatic steatosis through inhibition of the transcription factor PPARα. Indeed, JNK1/2 deficiency in hepatocytes protects against the development of steatosis, suggesting that JNK inhibition represents a possible treatment for this disease. However, the long-term consequences of JNK inhibition have not been evaluated. Here we demonstrate that hepatic JNK controls bile acid production. We found that hepatic JNK deficiency alters cholesterol metabolism and bile acid synthesis, conjugation, and transport, resulting in cholestasis, increased cholangiocyte proliferation, and intrahepatic cholangiocarcinoma. Gene ablation studies confirmed that PPARα mediated these effects of JNK in hepatocytes. This analysis highlights potential consequences of long-term use of JNK inhibitors for the treatment of metabolic syndrome.

Dual Targeting of G9a and DNA Methyltransferase‐1 for the Treatment of Experimental Cholangiocarcinoma

“…The Jnk hepa mice, in a C57BL/6J background, were generated as previously described (19,20). At 14 days of age mice received 25mg/kg (i.p.)…”

JNK signaling prevents biliary cyst formation through a CASPASE-8–dependent function of RIPK1 during aging

“…We identified these cysts as focal dilated duct structures which were morphologically connected and originated from the intrahepatic bile duct system. Of note, we could not detect neoplastic or dysplastic areas, arguing against the development of an intrahepatic cholangiocarcinoma (iCCA) or any iCCA precursor lesions ( 37 ). The cyst fluid of JNK1/2 LPC-KO mice contained a serum-like protein pattern, which is similar to a protein profile found in human biliary cysts ( 14 ).…”

Hydrogen gas alleviates acute alcohol‑induced liver injury by inhibiting JNK activation

“…Acute ethanol loading causes oxidative stress and activates cell-death signaling through the JNK pathway in the liver ( 31 ). In addition, JNK is a key mediator in hepatic steatosis, where it regulates transcription factor activity associated with lipid metabolism ( 32 , 33 ). In the present study, the upregulation of serum ALT and AST levels after ethanol treatment indicated hepatocytes damage.…”

“…JNK activation can cause programmed cell death, and increases the expression of lipogenic transcription factor sterol regulatory element binding protein (SREBP)-activated lipid synthesis enzymes, resulting in hepatic steatosis ( 31 , 33 , 40 , 41 ). Additionally, JNK may suppress hepatic peroxisome proliferator-activated receptor-α (PPAR-α) activation, which is a transcription factor and a positive regulator of intracellular free fatty acid and TG metabolism by regulating gene transcription involved in fatty acid transport and degradation in mitochondria and peroxisomes ( 32 ). Therefore, hepatic JNK activation increases oxidative stress, leads to hepatocyte apoptosis and injury, and contributes to hepatic steatosis via modulating lipid metabolic transcription factor activation.…”