Receptor interacting protein 3 protects mice from high‐fat diet‐induced liver injury
详细信息 查看全文
- 作者：Sanjoy Roychowdhury ; Rebecca L. McCullough ; Carlos Sanz‐Garcia ; Paramananda Saikia ; Naim Alkhouri ; Ammar Matloob ; Katherine A. Pollard ; Megan R. McMullen ; Colleen M. Croniger ; Laura E. Nagy
- 刊名：Hepatology
- 出版年：2016
- 出版时间：November 2016
- 年：2016
- 卷：64
- 期：5
- 页码：1518-1533
- 全文大小：1.5MB
- ISSN：1527-3350
文摘
Multiple pathways of programmed cell death are important in liver homeostasis. Hepatocyte death is associated with progression of nonalcoholic fatty liver disease, and inhibition of apoptosis partially protects against liver injury in response to a high-fat diet (HFD). However, the contribution of necroptosis, a caspase-independent pathway of cell death, to HFD-induced liver injury is not known. Wild-type C57BL/6 and receptor interacting protein (RIP) 3−/− mice were randomized to chow or HFD. HFD-fed C57BL/6 mice increased expression of RIP3, the master regulator of necroptosis, as well as phosphorylated mixed lineage kinase domain-like, an effector of necroptotic cell death, in liver. HFD did not increase phosphorylated mixed lineage kinase domain-like in RIP3−/− mice. HFD increased fasting insulin and glucose, as well as glucose intolerance, in C57BL/6 mice. RIP3−/− mice were glucose-intolerant even on the chow diet; HFD further increased fasting glucose and insulin but not glucose intolerance. HFD also increased hepatic steatosis, plasma alanine aminotransferase activity, inflammation, oxidative stress, and hepatocellular apoptosis in wild-type mice; these responses were exacerbated in RIP3−/− mice. Importantly, increased inflammation and injury were associated with early indicators of fibrosis in RIP3−/− compared to C57BL/6 mice. Culture of AML12 hepatocytes with palmitic acid increased cytotoxicity through apoptosis and necrosis. Inhibition of RIP1 with necrostatin-1 or small interfering RNA knockdown of RIP3 reduced palmitic acid-induced cytotoxicity. Conclusion: Absence of RIP3, a key mediator of necroptosis, exacerbated HFD-induced liver injury, associated with increased inflammation and hepatocyte apoptosis, as well as early fibrotic responses; these findings indicate that shifts in the mode of hepatocellular death can influence disease progression and have therapeutic implications because manipulation of hepatocyte cell death pathways is being considered as a target for treatment of nonalcoholic fatty liver disease. (Hepatology 2016;64:1518-1533)