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| Status |
Public on Jun 05, 2024 |
| Title |
Membrane phospholipid remodeling modulates nonalcoholic steatohepatitis progression by regulating mitochondrial homeostasis. |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Background and aims: NASH, characterized by inflammation and fibrosis, is emerging as a leading etiology of HCC. Lipidomics analyses in the liver have shown that the levels of polyunsaturated phosphatidylcholine (PC) are decreased in patients with NASH, but the roles of membrane PC composition in the pathogenesis of NASH have not been investigated. Lysophosphatidylcholine acyltransferase 3 (LPCAT3), a phospholipid (PL) remodeling enzyme that produces polyunsaturated PLs, is a major determinant of membrane PC content in the liver.
Approach and results: The expression of LPCAT3 and the correlation between its expression and NASH severity were analyzed in human patient samples. We examined the effect of Lpcat3 deficiency on NASH progression using Lpcat3 liver-specific knockout (LKO) mice. RNA sequencing, lipidomics, and metabolomics were performed in liver samples. Primary hepatocytes and hepatic cell lines were used for in vitro analyses. We showed that LPCAT3 was dramatically suppressed in human NASH livers, and its expression was inversely correlated with NAFLD activity score and fibrosis stage. Loss of Lpcat3 in mouse liver promotes both spontaneous and diet-induced NASH/HCC. Mechanistically, Lpcat3 deficiency enhances reactive oxygen species production due to impaired mitochondrial homeostasis. Loss of Lpcat3 increases inner mitochondrial membrane PL saturation and elevates stress-induced autophagy, resulting in reduced mitochondrial content and increased fragmentation. Furthermore, overexpression of Lpcat3 in the liver ameliorates inflammation and fibrosis of NASH.
Conclusions: These results demonstrate that membrane PL composition modulates the progression of NASH and that manipulating LPCAT3 expression could be an effective therapeutic for NASH.
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| Overall design |
Both Lpcat3 liver knockout (LKO) and control mice fed with NASH diet for 12 weeks were used for liver RNA sequencing. LKO and Con groups contain 5 mice each (GSM6734249-GSM6734258). Lpcat3 vs eGFP are mice injected with AAV expressing either eGFP control or Lpcat3 for overexpression. Mice were fed with NASH diet before RNA sequencing. Detailed study design was discussed in the paper (PMID: 36999536).
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| Citation(s) |
36999536 |
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| Submission date |
Nov 16, 2022 |
| Last update date |
Jun 05, 2024 |
| Contact name |
Ye Tian |
| E-mail(s) |
yet4@illinois.edu
|
| Phone |
2178196130
|
| Organization name |
University of Illinois ar Urbana-Champaign
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| Department |
Comparative Biosciences
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| Street address |
2001 South Lincoln Avenue, room 3612
|
| City |
Urbana |
| State/province |
IL |
| ZIP/Postal code |
61801 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (18)
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| This SuperSeries is composed of the following SubSeries: |
| GSE218073 |
Membrane phospholipid remodeling modulates nonalcoholic steatohepatitis progression by regulating mitochondrial homeostasis [LKO_NASH] |
| GSE218074 |
Membrane phospholipid remodeling modulates nonalcoholic steatohepatitis progression by regulating mitochondrial homeostasis [Lpcat3_OE] |
|
| Relations |
| BioProject |
PRJNA902270 |
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