Caspase Recruitment Domain Protein 6 Protects Against Hepatic Steatosis and Insulin Resistance by Suppressing Apoptosis Signal–Regulating Kinase 1

Abstract

The rapidly increasing prevalence of metabolic disorders associated with nonalcoholic fatty liver disease (NAFLD) warrants further study of the underlying mechanisms to identify key regulators as targets for the development of therapeutic interventions. Caspase recruitment domain protein 6 (Card6), as a member of the CARD family that regulates cell death and immunity, may potentially control this process. Indeed, Card6 down-regulation was found to be closely associated with the fatty livers observed in NAFLD patients, obese mice, and a palmitate-treated hepatocyte model. Gain-of-function and loss-of-function Card6 mouse models demonstrated that Card6 protected mice from insulin resistance, hepatic steatosis, and inflammatory responses upon high-fat diet administration. Mechanistically, Card6 interacted with and inhibited apoptosis signal-regulating kinase 1 (Ask1) and its subsequent downstream c-Jun N-terminal kinase/p38 signaling. Furthermore, Ask1 was sufficient to mediate Card6 function, and the interaction between Ask1 and Card6 was absolutely required for Card6 function in vivo. Adenovirus-mediated Card6 overexpression in the liver effectively ameliorated insulin resistance and hepatic steatosis in ob/ob mice. Therefore, we identified Card6 as an important negative regulator in NAFLD. Conclusion: Targeting Ask1 by Card6 may be a good strategy to develop a therapeutic method against NAFLD.

Dual Specificity Phosphatase 12 Regulates Hepatic Lipid Metabolism Through Inhibition of the Lipogenesis and Apoptosis Signal–Regulating Kinase 1 Pathways

“…ASK1 is a MAPK kinase kinase that was identified as an activator of the MKK4/7–JNK and MKK3/6–p38 pathways, resulting in apoptosis . Recently, a large number of studies have indicated a critically exacerbated role of ASK1 activation in the progression of NAFLD and NASH . Importantly, hyperactivated ASK1 was detected in human subjects with NASH, which further supports the potential clinical use of ASK1 as a therapeutic target for NASH.…”

Coreopsis Tinctoria Modulates Lipid Metabolism by Decreasing Low-Density Lipoprotein and Improving Gut Microbiota

“…Liver histology indicated that oral feeding of CT improved liver lobular structure and attenuated liver cell steatosis. There were no significant alterations of serum ALT or AST levels among the three groups, although there was a slight increase in serum ALT and AST levels (within a normal range of variation [35,36]) from the NC group relative to the HL and CT groups. These data indicated that there was no damage to liver function after oral administration of CT to reduce serum lipid levels.…”

Targeting CARD6 attenuates spinal cord injury (SCI) in mice through inhibiting apoptosis, inflammation and oxidative stress associated ROS production

“…Recently, CARD6 was reported to protect against cardiac hypertrophy in response to pressure overload by regulating mitogen-activated protein kinases (MAPKs) signaling pathway [17]. Furthermore, CARD6-knockout mice exhibited severer fatty livers, which was partly associated with the excessive activation of NF-κB signaling [19]. Similarly, CARD6 efficiently protected against hepatic I/R injury through decreasing the release of inflammatory cytokines, blocking NF-κB signaling and ameliorating the cell death [18].…”

“…Excessive inflammation is involved in SCI progression, and CARD6 was previously suggested to modulate inflammatory response [18,19]. Thus, we subsequently attempted to explore if CARD6 could modulate inflammation to regulate SCI development.…”