ABSTRACT
Abstract .................................................................................................................. 365 Introduction ............................................................................................................366 Mitochondria and JNK Activation in Lipotoxicity ................................................ 367 Fatty Acid Oxidation and Mitochondria Respiration ............................................. 369 Endoplasmic Reticulum Stress and JNK Activation in Lipotoxicity ..................... 370 ROS and JNK Activation in Lipotoxicity .............................................................. 371 Role of JNK Signaling to Mitochondria in Lipotoxicity ....................................... 373 Acknowledgments .................................................................................................. 375 References .............................................................................................................. 375
The fatty accumulation in the liver (hepatic steatosis) is referred to nonalcoholic fatty liver disease (NAFLD). Approximately, 20% of the U.S. population suffers from NAFLD, and the prevalence is increasing [1]. The exact reasons and mechanisms by which the disease progresses from hepatic steatosis to NASH, characterized by hepatic inammation and brosis, are not known. The potential causes of hepatic inammation in the development of steatohepatitis include oxidative stress, adipose tissue-derived cytokines, or translocation of endotoxin from the intestinal lumen, all of which may induce this “second hit” phenomenon superimposed on NAFLD [2]. The activities of JNK in the liver, accompanied by the adipose tissues and muscles, are believed to be important in the development of NAFLD and NASH. JNK plays a major role in the mechanism of lipotoxicity. The mechanism of lipotoxicity-induced mitochondrial dysfunction has been investigated with saturated fatty acids, such as palmitic acid (PA) [3-11]. Strong activation of JNK has been observed in the liver, fat, and muscle tissues in mice placed on a high-fat diet (HFD) and genetically (ob/ob) obese mice [3,12,13]. We previously demonstrated that sustained JNK activation and cell death in several models of hepatotoxicity, such as acetaminophen overdose, TNF/galactosamine, and tunicamycin-induced ER stress, depends on the expression of Sab, a mitochondrial JNK docking protein [14,15]. We also demonstrated that the addition of P-JNK plus ATP, but not either alone, to isolated hepatic mitochondria induced an inhibition of respiration and enhanced ROS production [15]. JNK activation is also associated with ER stress-mediated insulin resistance. ER stress causes JNK activation through ASK1 association with IRE1 [15,16]. However, the ER stress induced by hepatic XBP-1 deciency is therefore not associated with JNK-mediated insulin resistance. In mouse hepatocytes, PA increased P-PERK and downstream target CHOP in PMH but failed to activate the IRE-1α arm of the UPR. The specic inhibition of PERK prevented JNK activation and cell death, indicating a major role upstream of JNK activation [9]. JNK activation partially depends on JIP1, a scaffold protein that contributes to insulin resistance and hepatic steatosis [17]. Double-stranded RNA-dependent protein kinase (PKR) is another upstream regulator of JNK that has been associated with metabolic disease. PKR senses high levels of nutrients and obese states to activate JNK, which causes insulin resistance and hepatic steatosis [18]. JNK activity regulates pathophysiologic processes, such as hepatocyte death, steatosis, inammation, and insulin resistance, which are associated with NASH, brosis, and hepatocellular carcinoma (HCC). Preclinical studies in animal models or human cells have indicated that reagents that inhibit JNK might be used to treat patients with liver diseases, including acute liver failure, I/R injury, brosis, HCC, and NASH [19-21]. Several JNK inhibitors, such as SP600125, D-JNKI1, and BI-78D3, have been tested in preclinical studies. CC-930 is currently being tested in a phase 2 clinical trial for idiopathic pulmonary brosis [22], and dual inhibitors of JIP and JNK have been identied [23]. Further work is required to assess new JNK inhibitors, alone or in combination with other therapeutics in the treatment and prevention of NASH, insulin resistance, and other liver diseases [24].
