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



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).
Department of Pathobiology, Cleveland Clinic, Cleveland, OH.|Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH.
Sanjoy
S
Roychowdhury
Department of Pathobiology, Cleveland Clinic, Cleveland, OH.
Rebecca L
RL
McCullough
Department of Pathobiology, Cleveland Clinic, Cleveland, OH.
Carlos
C
Sanz-Garcia
Department of Pathobiology, Cleveland Clinic, Cleveland, OH.
Paramananda
P
Saikia
Department of Gastroenterology, Cleveland Clinic, Cleveland, OH.|Department of Pediatric Gastroenterology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH.
Naim
N
Alkhouri
Department of Pediatric Gastroenterology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH.
Ammar
A
Matloob
Department of Pathobiology, Cleveland Clinic, Cleveland, OH.
Katherine A
KA
Pollard
Department of Pathobiology, Cleveland Clinic, Cleveland, OH.
Megan R
MR
McMullen
Department of Nutrition, Case Western Reserve University, Cleveland, OH.
Colleen M
CM
Croniger
Department of Pathobiology, Cleveland Clinic, Cleveland, OH. nagyL3@ccf.org.|Department of Gastroenterology, Cleveland Clinic, Cleveland, OH. nagyL3@ccf.org.|Department of Nutrition, Case Western Reserve University, Cleveland, OH. nagyL3@ccf.org.|Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH. nagyL3@ccf.org.
Laura E
LE
Nagy
D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D059305:Diet, High-Fat; D022781:Hepatocytes; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000517:prevention & control; D011897:Random Allocation; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000502:physiology*
D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse