RIPK3 dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease

Abstract

Background and Aims: Receptor-interacting protein kinase 3 (RIPK3) mediates NAFLD progression, but its metabolic function is unclear. Here, we aimed to investigate the role of RIPK3 in modulating mitochondria function, coupled with lipid droplet (LD) architecture in NAFLD. Approach and Results:Functional studies evaluating mitochondria and LD biology were performed in wild-type (WT) and Ripk3 −/− mice fed a cholinedeficient, amino acid-defined (CDAA) diet for 32 and 66 weeks and in CRISPR-Cas9 Ripk3-null fat-loaded immortalized hepatocytes. The association between hepatic perilipin (PLIN) 1 and 5, RIPK3, and disease severity was also addressed in a cohort of patients with NAFLD and in PLIN1-associated

Mediators of necroptosis: from cell death to metabolic regulation

“…Moreover, Rip3 deficiency influences the hepatic lipidome in the context of choline-deficient amino acid (CDAA) diet-induced steatohepatitis through the up-regulation of peroxisome proliferator-activated receptor gamma (PPARγ) (Afonso et al, 2021 ). Functional studies in mice and hepatocytes provide insights into the role of RIP3 in mitochondrial and lipid droplet (LD) biology (Afonso et al, 2023 ; Islam et al, 2022 ). RIP3 interacts with key mitochondrial constituents, such as voltage-dependent anion channel (VDAC), mitochondrial antiviral-signaling protein (MAVS), mitochondrial permeability transition pore (mPTP), and metabolic enzymes including pyruvate dehydrogenase (PDH), glycogen phosphorylase (PYGL), glutamate-ammonia ligase (GLUL), and glutamate dehydrogenase 1 (GLUD1) (Islam et al, 2022 ; Qiu et al, 2018 ; Yang et al, 2018 ).…”

“…These interactions play a role in modulating mitochondrial function and lipid metabolism. The association between RIP3, perilipins (PLIN1 and PLIN5), and disease severity has been demonstrated in patients with MASLD and familial partial lipodystrophy (Afonso et al, 2023 ). Notably, Rip3 deficiency improves mitochondrial function and enhances antioxidant systems, reducing stress during lipid overload (Afonso et al, 2023 ; Conway et al, 1988 ).…”

RIPK3 signaling and its role in regulated cell death and diseases

“…Excess RIPK3 aggravates the disease and enhances inflammatory responses by regulating the activation of mitophagy [ 76 ]. In addition, RIPK3 is overexpressed in patients with nonalcoholic steatohepatitis (NASH) and is associated with liver inflammation and fibrosis [ 77 ]. Deletion of RIPK3 has been shown to alleviate CDAA-induced inflammation and fibrosis in mice [ 78 ].…”

Spatial metabolomics and its application in the liver

“…[118][119][120] By combining genetic and dietary murine models of NAFLD, the role of receptorinteracting protein 3 in NAFLD pathophysiology was demonstrated, [121] which impacted necroptosis and hepatic lipid profiles associated with NAFLD. [122,123] Animal models have also been used to deepen the knowledge of organ-organ communication and its impact on liver metabolism, where the relevance of the gut microbiota is emerging. Changes in mouse gut microbiota and metabolites can drive NAFLD progression to HCC.…”

“…Considering that around 40% of cases with NASH progress to liver fibrosis, a significant risk factor for HCC development 117 understanding the molecular changes at the metabolic and lipidic levels is paramount for disease diagnosis and management, where metabolomic-based and lipidomic-based approaches have been increasingly used 118–120 . By combining genetic and dietary murine models of NAFLD, the role of receptor-interacting protein 3 in NAFLD pathophysiology was demonstrated, 121 which impacted necroptosis and hepatic lipid profiles associated with NAFLD 122,123 . Animal models have also been used to deepen the knowledge of organ-organ communication and its impact on liver metabolism, where the relevance of the gut microbiota is emerging.…”