Hepatic Regulator of G Protein Signaling 6 (RGS6) drives non-alcoholic fatty liver disease by promoting oxidative stress and ATM-dependent cell death

Abstract

The pathophysiological mechanism(s) driving non-alcoholic fatty liver disease, the most prevalent chronic liver disease globally, have yet to be fully elucidated. Here, we identify regulator of G protein signaling 6 (RGS6), up-regulated in the livers of NAFLD patients, as a critical mediator of hepatic steatosis, fibrosis, inflammation, and cell death. Human patients with high hepatic RGS6 expression exhibited a corresponding high inflammatory burden, pronounced insulin resistance, and poor liver function. In mice, liver-specific RGS6 knockdown largely ameliorated high fat diet (HFD)-driven oxidative stress, fibrotic remodeling, inflammation, lipid deposition and cell death. RGS6 depletion allowed for maintenance of mitochondrial integrity restoring redox balance, improving fatty acid oxidation, and preventing loss of insulin receptor sensitivity in hepatocytes. RGS6 is both induced by ROS and increases ROS generation acting as a key amplification node to exacerbate oxidative stress. In liver, RGS6 forms a direct complex with ATM kinase supported by key aspartate residues in the RGS domain and is both necessary and sufficient to drive hyperlipidemia-dependent ATM phosphorylation. pATM and markers of DNA damage (γH2AX) were also elevated in livers from NAFLD patients particularly in samples with high RGS6 protein content. Unsurprisingly, RGS6 knockdown prevented ATM phosphorylation in livers from HFD-fed mice. Further, RGS6 mutants lacking the capacity for ATM binding fail to facilitate palmitic acid-dependent hepatocyte apoptosis underscoring the importance of the RGS6-ATM complex in hyperlipidemia-dependent cell death. Inhibition of RGS6, then, may provide a viable means to prevent or reverse liver damage by mitigating oxidative liver damage.

Identification of shared genetic architecture between non-alcoholic fatty liver disease and type 2 diabetes: A genome-wide analysis

“…Studies have shown that FOXN3 suppresses the mRNA and protein expression of E2F5 by inhibiting the promoter activity of potential oncogene E2F5 , thereby inhibiting the proliferation of HCC cells in vitro and in vivo ( 43 ). Another tumor suppressor, regulator of G protein signaling 6 ( RGS6 ), is upregulated in the liver of NAFLD patients, forms a complex with ATM in the liver, promotes ATM phosphorylation, and drives hepatic steatosis ( 44 , 45 ). A study confirmed that hepatic RGS6 increases oxidative stress and inflammation, which drive lipid deposition, fibrosis, and nonalcoholic fatty liver disease ( 46 ).…”

TXNIP in liver sinusoidal endothelial cells ameliorates alcohol-associated liver disease

“…Suppression of TAK1 and its downstream signaling significantly promotes liver injury, inflammation, fibrosis, and tumor formation (Inokuchi et al ., 2010; Tan et al ., 2020). TAK1 hyperactivation, on the other hand, induces hepatic steatosis, inflammation, and fibrosis, whereas TAK1 activity suppression alleviates the progression of these diseases (Inokuchi et al ., 2010; Mahata et al , 2021; Qian et al ., 2022; Zhang et al ., 2022). Here, TAK1 inhibition attenuated JNK activation, restored the eNOS level, and down-regulated cytokines and adhesion molecule in Txnip -deficient LSECs.…”

RGS11-CaMKII complex mediated redox control attenuates chemotherapy-induced cardiac fibrosis

“…More specifically, Gβ 5 KD in murine VCM blocks doxorubicin- and 5-FU-driven phosphorylation of both ATM and CaMKII. RGS6, which forms a direct complex with ATM [ 36 ] is required for activation of the ATM/p53 signaling cascade in VCM exposed to doxorubicin [ 31 ], but the R7 family member responsible for CaMKII regulation had yet to be identified. Indeed, the fact that Gβ 5 expression is not completely absent from the hearts of RGS6 −/− mice [ 56 , 57 ] indicates that another R7 family member is also present in the myocardium.…”

“…The full-length RGS11 and CaMKIIδ coding sequences were amplified by PCR from human blood cDNA according to our published method [ 36 ]. RGS11 and CaMKIIδ deletion & point mutation sequences were generated by overlapping primer-based PCR amplification and cloned into the pEGFP-N1 vector or pCMV-HA-N vectors, respectively.…”