RIPK3 acts as a lipid metabolism regulator contributing to inflammation and carcinogenesis in non-alcoholic fatty liver disease

Abstract

ObjectiveReceptor-interacting protein kinase 3 (RIPK3) is a key player in necroptosis execution and an emerging metabolic regulator, whose contribution to non-alcoholic fatty liver disease (NAFLD) is controversial. We aimed to clarify the impact of RIPK3 signalling in the pathogenesis of human and experimental NAFLD.DesignRIPK3 levels were evaluated in two large independent cohorts of patients with biopsy proven NAFLD diagnosis and correlated with clinical and biochemical parameters. Wild-type (WT) or Ripk3-deficient (Ripk3−/−) mice were fed a choline-deficient L-amino acid-defined diet (CDAA) or an isocaloric control diet for 32 and 66 weeks.ResultsRIPK3 increased in patients with non-alcoholic steatohepatitis (NASH) in both cohorts, correlating with hepatic inflammation and fibrosis. Accordingly, Ripk3 deficiency ameliorated CDAA-induced inflammation and fibrosis in mice at both 32 and 66 weeks. WT mice on the CDAA diet for 66 weeks developed preneoplastic nodules and displayed increased hepatocellular proliferation, which were reduced in Ripk3−/− mice. Furthermore, Ripk3 deficiency hampered tumourigenesis. Intriguingly, Ripk3−/− mice displayed increased body weight gain, while lipidomics showed that deletion of Ripk3 shifted hepatic lipid profiles. Peroxisome proliferator-activated receptor γ (PPARγ) was increased in Ripk3−/− mice and negatively correlated with hepatic RIPK3 in patients with NAFLD. Mechanistic studies established a functional link between RIPK3 and PPARγ in controlling fat deposition and fibrosis.ConclusionHepatic RIPK3 correlates with NAFLD severity in humans and mice, playing a key role in managing liver metabolism, damage, inflammation, fibrosis and carcinogenesis. Targeting RIPK3 and its intricate signalling arises as a novel promising approach to treat NASH and arrest disease progression.

Analysis of Common Pathways and Markers From Non-Alcoholic Fatty Liver Disease to Immune-Mediated Diseases

“…This process is initiated by death receptors or PPRs, including TLRs, and needs from RIPK1 and RIPK3 proteins to be executed, among others ( 48 ). RIPK3 has emerged as a metabolic regulator and its role as a key manager of metabolism, damage, inflammation, fibrosis and even carcinogenesis has been recently proven ( 49 ).…”

The role of RIPK3 in liver mitochondria bioenergetics and function

“…10 Accordingly, we have recently shown that Ripk3-deficient mice display increased levels of liver glycogen compared with wild-type counterparts upon a dietary model of NAFLD. 26 RIPK3 also directly targets and activates glutamate ammonia ligase (GLUL) and glutamate dehydrogenase 1 (GLUD1), which catalyses the conversion of glutamate and ammonia to glutamine in cytosol and glutamate to α-ketoglutarate in mitochondria, respectively. In turn, both α-ketoglutarate and glutamine metabolism also feed the TCA cycle, powering OXPHOS and overproduction of the oxidative metabolism product, ROS.…”

“…Further, we have recently shown that RIPK3 depletion in mice is associated with increased activity of liver MRC complexes in experimental NASH, with the concomitant increase of citrate synthase activity, a TCA enzyme, 5 but strikingly this phenotype was accompanied by decreased ROS production. 26 With the restoration of defective MRC complex activity in Ripk3-deficient mice, overall mitochondrial metabolic homeostasis was also enhanced by Ripk3 deficiency, followed by increased mitochondrial biogenesis and fatty-oxidation markers. 5 Thus, activation of MRC complexes is a novel indication of RIPK3-mediated mitochondrial energy metabolism regulation, considering the central role of MRC complexes on the electron transport chain and that defects in MRC complexes lead to ROS overabundance.…”

“…21,22 A growing body of evidence has shown that RIPK3mediated aberrant necroptosis is closely inter-linked with many human pathologies, 13,23 including chronic liver disease, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and associated hepatocellular carcinoma (HCC). 5,[24][25][26][27][28] Furthermore, in the context of NAFLD and NASH, we have recently reported RIPK3 as an energy and lipid metabolism regulator, where at least part of its effect was mediated through modulation of mitochondrial function. 5,26 In this review, we discuss the key role of RIPK3 in mitochondrial bioenergetics, cellular necroptosis and liver diseases.…”

“…5,[24][25][26][27][28] Furthermore, in the context of NAFLD and NASH, we have recently reported RIPK3 as an energy and lipid metabolism regulator, where at least part of its effect was mediated through modulation of mitochondrial function. 5,26 In this review, we discuss the key role of RIPK3 in mitochondrial bioenergetics, cellular necroptosis and liver diseases. Particularly, we focus on metabolic liver disease and the potential translation of drug targets and biomarkers into applications.…”