The liver is the largest solid organ in the body, accounting for about 2% of an adult's body weight. The liver has multiple biological functions that are critical to maintaining homeostasis and maintaining metabolic balance, including the metabolism of nutrients, the breakdown of toxic substances, and the synthesis of various proteins [1]. The liver receives a dual blood supply. About a quarter of the liver's blood comes from the hepatic artery, which has a high blood oxygen content and provides oxygen for the liver's metabolism. About three-quarters of the remaining blood in the liver comes from the portal vein. As the portal vein is located downstream of the gastrointestinal tract, its blood contains various nutrients, pathogenic microorganisms and other antigens absorbed by the small intestine[2, 3]. Therefore, the liver is constantly exposed to this complex immune environment. Under normal physiological conditions, the immune system of the liver can treat different antigenic substances differently to maintain immune balance, indicating the existence of specific immune rejection and immune tolerance mechanisms in the liver.
Autoimmune hepatitis occurs when autoreactive T cells destroy liver or bile duct cells in autoimmune diseases, and when virus-specific T cells destroy infected liver cells in viral hepatitis[4]. This is due to inflammation and injury caused by continuous recruitment and activation of effector leukocytes in inflammatory liver[5]. However, as the underlying pathophysiological mechanism remains unclear, there is no clear and effective treatment strategy.
About 350 million people in the world currently suffer from liver disease and more than 1 million die from it each year. China is a high incidence area of hepatitis, hepatitis B virus carrying rate is very high, up to 11 percent[6]. Because liver diseases are difficult to cure and easy to relapse, most patients with liver disease eventually face serious liver diseases such as cirrhosis and liver cancer, which poses a great threat to life safety [7]. In the occurrence and development of liver diseases, most of them involve immune liver injury. Among them, autoimmune hepatitis is the main immune liver injury, and autoimmune hepatitis (AIH) is a chronic progressive hepatitis, which is characterized by elevated liver aminotransferase, the autoimmune lobular structure disorder, inflammation, and lymphocyte infiltration[8]. In recent years, with the deepening of the understanding of autoimmune hepatitis, the research on AIH at home and abroad is becoming mature. AIH presents a global distribution, with different incidence rates due to regional and ethnic differences, with the highest prevalence in North America and East Asia [9]. Because the diagnosis is often ignored, the epidemiological data are different, but with the increasing prevalence of AIH in China, AIH has gradually attracted people's attention [10]. AIH is a chronic progressive liver inflammatory disease mediated by autoimmune response that is common in the world. The main clinical manifestations are: elevated serum transaminase, hypergamma-globulinemia, positive auto-antibodies, inflammatory cell infiltration in the portal area, interfacial hepatitis of liver tissue, etc [5]. AIH primarily affects women, with a male-to-female ratio of about 1:4. AIH can occur in population of all ages and ethnicities, and severe cases can rapidly progress to cirrhosis and liver failure [9]. At present, the clinical treatment of AIH is mainly glucocorticoid and immunosuppressant [11]. Although these drugs can effectively relieve the disease of patients, they are prone to relapse and accompanied by more side effects after drug withdrawal, and the overall therapeutic effect is not ideal [3, 12, 13]. Therefore, it is urgent to find the main pathogenesis of AIH and new effective therapeutic strategies. Both genetic and environmental factors may be involved in the disease process, so the cause of AIH is unknown.
Nonalcoholic fatty liver disease (NAFLD), characterized by excessive TG and oxidative stress in the liver, is the hepatic manifestation of metabolic syndrome. It encompasses a disease spectrum from simple steatosis (TG accumulation in hepatocytes) to nonalcoholic steatohepatitis (NASH), fifibrosis, irreversible cirrhosis and even hepatocellular carcinoma and has been recognized as the leading cause of chronic liver disease [2, 14, 15]. It has not been reported whether high-fat diet (HFD), which causes the NAFLD, could affect AIH so far.
The main function of PPARα in liver is to regulate fatty acid oxidation metabolism and energy consumption [16, 17]. There are three pathways of fatty acid oxidation metabolism in liver: mitochondrial β-oxidation, peroxisome β-oxidation and microsomal/endoplasmic reticulum ω-oxidation [18]. Some key enzymes in these three fatty acid oxidative metabolic pathways all have PPRE elements and are mainly regulated by PPARα [10]. At present, the molecular mechanism of whether PPARα can be involved in the regulation of the occurrence and development of AIH remains unclear.
C-jun amino-terminal kinase (JNK) is one of the important members of the mitogen activated protein kinase family [19, 20]. In unstimulated cells, JNK mainly exists in the cytoplasm and has a certain distribution in the nucleus. When stimulated, JNK rapidly and significantly accumulates in the nucleus and causes changes in the expression of corresponding genes [21]. JNK signaling pathway can be activated by cytokines, hormones, metabolic pressure of cells, ionizing radiation, pathogenic microorganisms, toxic substances, oxidative damage and other factors, affecting cell proliferation, cell apoptosis, stress response, and participating in the occurrence and development of a variety of human diseases, including liver failure [5, 22]. Sabode et al. reported that p-JNK played a necessary pro-inflammatory role in the process of acute liver failure induced by acetaminophen. Wang et al. indicated that activation of JNK could promote GalN/LPS induced acute liver injury in mice [4, 9]. In addition, Chen et al. showed that activation of JNK signaling pathway can accelerate ConA-induced acute liver failure in mice [23, 24]. In conclusion, JNK may be involved in the induction of acute liver failure in mice and promote the progression of inflammatory response.
In our study, we deeply explored the relationship between PPARα, HFD and AIH, as well as how PPARα and HFD regulate the occurrence and development of AIH, so as to provide theoretical basis and experimental basis for the treatment of AIH in the future.