Nonalcoholic fatty liver disease (NAFLD) and its progressive forms of nonalcoholic steatohepatitis (NASH) are rapidly becoming a major cause of hepatocellular carcinoma. Currently, there are no approved therapies for the treatment of NASH. DEAD-box protein 5 (DDX5) plays an important role in different cellular processes. However, the exact role of DDX5 in NASH remains unclear.
On July 7, 2022, Kong Lingyi and Zhang Hao of China Pharmaceutical University published a joint newsletter at Hepatology online entitled "RNA helicase DEAD-box protein 5 alleviates nonalcoholic steatohepatitis progression via tethering TSC complex and suppressing mTORC1." signaling" research paper, which found that DDX5 is downregulated in the liver of NASH patients and mouse models, as well as in palmitic acid (PA)-stimulated liver cells. Adeno-associated virus (AAV)-mediated overexpression of DDX5 improves liver steatosis and inflammation, and its absence can worsen such pathologies. The mechanism of action of DDX5 in NASH and NASH-HCC was studied by non-targeted metabolomics analysis, suggesting the regulatory effect of DDX5 on lipid metabolism. DDX5 inhibits mTORC1 activation by recruiting TSC1/2 complexes to mTORC1, thereby improving lipid metabolism and attenuating NLRP3 inflammatory activation. The study further identified the phytochemical compound HK interacting directly with DDX5 and preventing its ubiquitination-induced degradation by the E3 ligase TRIM5, thereby significantly reducing lipid accumulation and inflammation in a mouse model of NASH.
Taken together, these findings provide new mechanistic insights into the role of DDX5 in mTORC1 regulation and NASH progression, and suggest a number of new targets and promising lead compounds for interventions to treat NASH.
In addition, on September 1, 2021, Kong Lingyi and Zhang Hao of China Pharmaceutical University jointly published a newsletter on Signal Transduction and Targeted Therapy (IF=38) entitled "LIX1-like protein drives hepatic stellate cell activation to promote liver fibrosis by regulation." Of chemokine mRNA stability" research paper that identifies LIX1L as a novel regulator that regulates liver fibrosis by activating HSCs during chronic liver injury. The interaction of LIX1L with CCL20 mRNA is a key molecular event that connects the CCL20-CCR6 axis, KCs-HSCs communication, and HSCs activation. Therefore, LIX1L suppression may be a promising strategy for preventing liver fibrosis (click to read).
Non-alcoholic fatty liver disease (NAFLD) has become a major cause of chronic liver disease, paralleling the global increase in diabetes and metabolic syndrome. Nonalcoholic steatohepatitis (NASH) is a progressive phase of NAFLD that can lead to liver fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). Currently, there is no FDA-approved treatment for NAFLD. Therefore, it is necessary to better understand the pathogenic mechanisms of NASH progression in order to design future treatments.
DEAD-box protein 5 (DDX5) is an ATP-dependent RNA helicase that is involved in many aspects of RNA metabolism and acts as a transcriptional-assisted modulator. DDX5 has been reported to negatively regulate Wnt signaling and enable STAT1 mRNA translation and interferon signaling in HBV replication cells, indicating that it has antitumor and antiviral effects. In HBV-associated HCC, decreased levels of the DDX5 and SUZ12 proteins are associated with viral transcriptional enhancement, increased viral replication, and poor prognosis in HCC patients. In addition, hepatic fibrosis is a marker of NASH progression, and DDX5 has been identified as an inhibitor of fibrosis genes in hepatic stellate cells. In obese mice induced by a high-fat diet, DDX5 was able to reduce insulin resistance. However, the exact role of DDX5 in NAFLD remains unclear.
mTORC1 consists of mTOR, RAPTOR, PRAS40, DEPTOR, and mLST8. In terms of mTORC1 regulation, the Tuberous Sclerosis Complex (TSC) is an isodimer consisting of TSC1 and TSC2 that acts as a negative regulator of mTORC1 signaling. The circadian rhythm protein Period2 has been reported to inhibit mTORC1 activity by recruiting TSC1 to the mTORC1 complex. Many studies have reported that mTORC1 is associated with the development and progress of NASH. Lipotoxicity caused by fatty acid (FA) accumulation activates mTORC1, thereby promoting liver steatosis. In addition, mTORC1 promotes metabolic reprogramming to accelerate obesity-associated liver cancer. However, the complex interaction of TSC1/2 and mTOR in the regulation of mTORC1 activity in NASH is unclear.
Article pattern diagram (from Hepatology)
mTOR is an important regulator of lipid homeostasis and autophagy. mTORC1 promotes devo fat production through a sterol regulatory element binding protein (SREBP) transcription factor that controls the expression of metabolic genes involved in FA synthesis. Lipid droplets can be degraded by autophagy, which is called autophagy. Autophagy has been reported to be impaired in the initial development and later progression of hepatic steatosis in NAFLD and NASH. Recent studies have shown that activation of mTORC1 inhibits fat phagocytosis and promotes steatosis, further exacerbating the development of NASH. Interestingly, by interrupting p62/TRAF6, DDX5 acts as an mTOR inhibitor and autophagy inducer. Therefore, the role of DDX5 in regulating mTOR signaling in NASH is of great interest.
TRIM5 is a RING domain-E3 ubiquitin ligase that plays a key role in innate immune signaling and antiviral host defense. TRIM5 may increase the likelihood of liver fibrosis after treatment in patients with HIV/HCV co-infection. A genome-wide association study of ALT, AST, ALP, and total bilirubin circulating levels identified TRIM5 as a risk factor for liver injury. However, whether TRIM5 was involved in the development of NASH remains unknown.
In this study, it was found that DDX5 was downregulated in the liver of NASH patients and mouse models, as well as in palmitic acid (PA)-stimulated liver cells. In addition, the study found that adeno-associated virus (AAV)-mediated overexpression of DDX5 improved liver steatosis, inflammation, and liver damage in mice, the absence of which worsened such pathologies. Mechanically, the study demonstrated that DDX5 inhibits mTORC1 activation by recruiting TSC1/2 complexes to mTORC1, improving lipid metabolism, and attenuating NLRP3 inflammatory activation.
The study further found that the phytochemical compound hyperforcinol K (HK) interacts directly with DDX5 and prevents its ubiquitination and degradation mediated by the E3 ligase TRIM5, thereby significantly reducing lipid accumulation and inflammation in a mouse model of NASH. These findings provide new mechanistic insights into the role of DDX5 in mTORC1 regulation and NASH progression, and suggest a number of new targets and promising pilot compounds for the treatment of NASH.
Informational messages:
https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.32651
Originated from [iNature]