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Role of SQSTM1/p62 in regulating Mallory-Denk body in alcohol-associated liver disease
Kaitlyn Hinz1, Hui Qian1, Brandon Peiffer2
1Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, USA.
Background:
Alcohol-associated liver disease (ALD) is a global health problem without an effective treatment. Mallory-Denk body (MDB) is a protein aggregate commonly found in alcohol-associated hepatitis (AH). MDB primarily contains ubiquitinated proteins, cytokeratin 8 and sequestosome 1 (SQSTM1)/p62. Stress granule (SG) is a cytosolic, membrane-less aggregate composed of various RNA-binding proteins and untranslated mRNA. However, the role and mechanisms of MDB and SG induced by alcohol and their implications in the pathogenesis of ALD remain largely unknown.
Methods:
SQSTM1/p62 whole body knockout and matched wild-type mice were subjected to the Gao-binge alcohol model or fed a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet alongside Gao-binge alcohol model. ALD mouse liver tissues and human AH liver tissues underwent immunohistochemistry (IHC) staining and western blot analysis for SG and MDB markers.
Results:
We found that the livers of patients with AH had higher levels of SQSTM1/p62 (MDB marker) and Ras-GTPase-activating protein-binding protein 1 (an SG marker) using IHC staining, and these increased protein levels were enriched in detergent-insoluble fractions compared with healthy individuals. We further discovered that Gao-binge alcohol feeding increased insoluble SG markers, such as phosphorylated eukaryotic initiation factor 2 in mouse livers. Mice fed a DDC diet with Gao-binge alcohol had greater hepatic MDB formation and liver injury than those fed either diet alone. Loss of SQSTM1/p62 led to reduced protein aggregation involved in SGs and MDBs but increased liver injury in DDC plus Gao-binge alcohol-fed mice, indicating that SQSTM1/p62 is required for MDB formation and protects against alcohol-induced liver injury.
Conclusion:
Chronic plus binge alcohol exposure increases hepatic MDBs and moderate levels of SGs. p62/SQSTM1 is critical for the formation but is not essential for the clearance of MDBs, a process that may act as an adaptive protective mechanism against ALD.
Insights
Alcohol-associated liver disease (ALD) involves Mallory-Denk bodies (MDBs) and stress granules (SGs). Sequestosome 1 (SQSTM1)/p62 is crucial for MDB formation, offering protection against ALD.
Area of Science:
- Hepatology
- Cellular Biology
- Biochemistry
Background:
- Alcohol-associated liver disease (ALD) is a significant global health issue with limited treatment options.
- Mallory-Denk bodies (MDBs), protein aggregates found in alcohol-associated hepatitis (AH), primarily consist of ubiquitinated proteins, cytokeratin 8, and sequestosome 1 (SQSTM1)/p62.
- The roles of MDBs and alcohol-induced stress granules (SGs) in ALD pathogenesis are not well understood.
Purpose of the Study:
- To investigate the role of SQSTM1/p62 in the formation of MDBs and SGs in alcohol-associated liver injury.
- To elucidate the mechanisms underlying MDB and SG formation in ALD.
- To determine the protective or detrimental effects of SQSTM1/p62 in ALD.
Main Methods:
- Utilized a mouse model of alcohol-induced liver injury (Gao-binge model) and a DDC diet model.
- Examined liver tissues from mice and human AH patients using immunohistochemistry and western blot for MDB and SG markers.
- Employed whole-body SQSTM1/p62 knockout mice to assess its specific role.
Main Results:
- Human AH livers showed increased SQSTM1/p62 (MDB marker) and Ras-GTPase-activating protein-binding protein 1 (SG marker) in detergent-insoluble fractions.
- Alcohol feeding increased insoluble SG markers in mouse livers.
- SQSTM1/p62 knockout mice exhibited reduced protein aggregation but exacerbated liver injury in combined alcohol and DDC diet models, indicating a protective role for SQSTM1/p62 in MDB formation against ALD.
Conclusions:
- Chronic plus binge alcohol exposure elevates hepatic MDBs and SGs.
- SQSTM1/p62 is essential for MDB formation, acting as a protective mechanism against alcohol-induced liver injury.
- While critical for MDB formation, SQSTM1/p62 is not essential for MDB clearance in ALD.
