Receptor interacting protein 3 protects mice from high‐fat diet‐induced liver injury

Abstract

Multiple pathways of programmed cell death are important in liver homeostasis. Hepatocyte death is associated with progression of nonalcoholic fatty liver disease (NAFLD) and inhibition of apoptosis partially protects against liver injury in response to high fat diets (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 (pMLKL), an effector of necroptotic cell death, in liver. HFD did not increase pMLKL in RIP3−/− mice. HFD increased fasting insulin and glucose, as well as glucose intolerance, in C57BL/6 mice. RIP3−/− were glucose intolerant even on chow diets; HFD further increased fasting glucose and insulin, but not glucose intolerance. HFD also increased hepatic steatosis, plasma ALT activity, inflammation, oxidative stress and hepatocellular apoptosis in wild-type mice; these responses were exacerbated in RIP3−/− mice. Importantly, increased inflammation and injury was associated with early indicators of fibrosis in RIP3−/− compared to C57BL/6 mice. Culture of AML12 hepatocytes with palmitic acid increased cytotoxicity via apoptosis and necrosis. Inhibition of RIP1 with necrostatin-1 or siRNA knock-down 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 NAFLD.

To die or not to die: death signaling in nonalcoholic fatty liver disease

“…This has led researchers to consider other types of cell death [123–125]. Treatment with palmitic acid induces not only apoptosis, but also an emerging type of cell death termed necroptosis [123, 124].…”

“…However, recent functional studies with RIP3 knockout mice have provided controversial results. Although RIP3 knockout mice were protected from NASH induced by an MCD diet [123, 124], HFD-induced liver injury and steatosis were exacerbated in RIP3-deficient mice [125]. Although both diets induce similar pathological features, their pathogenic mechanisms are quite distinct.…”

Gold-quercetin nanoparticles prevent metabolic endotoxemia-induced kidney injury by regulating TLR4/NF-kB signaling and Nrf2 pathway in high fat diet fed mice

“…[1][2][3] Lately, high-fat diet (HFD)-induced inflammatory responses in the peripheral tissues, especially in liver, cardiac muscle, and kidney, have been well characterized. [4][5][6] In a previous research, HFD was found to be capable of causing 3 CKD, a progressive loss in renal function over a period of months or years, has been regarded as a threat to people all over the world. 7,8 As the final manifestation of CKD, renal fibrosis is a common pathway toward kidney failure.…”

A murder mystery in the liver: who done it and how?

“…The latter result is intriguing, as RIPK3, the only identified kinase capable of activating MLKL, is not detectable in normal hepatocytes (8,13). RIPK3 induction has been suggested to occur in chronic liver injury, such as alcoholic and nonalcoholic steatohepatitis; however, actual necroptosis due to putative induction of RIPK3 in the liver has not been convincingly demonstrated (14)(15)(16). Hepatocytes do express MLKL, though at lower levels than nonparenchymal cells, making MLKL-induced cell death a possibility (8).…”