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Aldehydes alter TGF-β signaling and induce obesity and cancer

ABSTRACT: Obesity and fatty liver diseases-metabolic dysfunction-associated steatotic liver disease (MASLD and MASH) affect over a third of the global population and are exacerbated in individuals with reduced functional aldehyde dehydrogenase 2 (ALDH2), observed in approximately 560 million people. Current treatment to prevent disease progression to cancer remains inadequate, requiring innovative approaches. We observe that Aldh2-/- and Aldh2-/-Sptbn1+/- (ASKO) mice develop phenotypes of human Metabolic Syndrome (MetS) and MASH with altered lipid metabolism and TGF-β signaling, leading to pro-fibrotic and pro-oncogenic phenotypes, which is restored to normal with siRNA to SPTBN1. Significantly, therapeutic inhibition of SPTBN1 blocks MASH and fibrosis in a human 3D MASH model. This study identifies SPTBN1 as a critical regulator of the functional phenotype of toxic aldehyde-induced MASH and a potential therapeutic target.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE273561 | GEO | 2024/08/06

REPOSITORIES: GEO

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	GSE273561_RAW.tar	Raw
	GSE273561_TPM_values_siCtrl_vs_25nM_siSptbn1_vs_50nM_siSptbn1_96h.txt.gz	Txt
	GSE273561_aggregation.csv.gz	Csv
	GSE273561_fpkm_WT_vs_KO_vs_double.txt.gz	Txt

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Aldehydes alter TGF-b signaling and induce obesity and cancer

Project description:Obesity and fatty liver diseases—metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH)—affect over one-third of the global population and are exacerbated in individuals with reduced functional aldehyde dehydrogenase 2 (ALDH2), observed in approximately 560 million people. Current treatment to prevent disease progression to cancer remains inadequate, requiring innovative approaches. We observe that Aldh2KO and Aldh2KO/Sptbn1 KO/WT mice develop phenotypes of human metabolic syndrome (MetS) and MASH with accumulation of endogenous aldehydes such as 4-hydroxynonenal (4-HNE). Mechanistic studies demonstrate aberrant transforming growth factor b (TGF-b) signaling through 4-HNE modification of the SMAD3 adaptor SPTBN1 (b2-spectrin) to proQ8 fibrotic and pro-oncogenic phenotypes, which is restored to normal with small interfering RNA (siRNA) to SPTBN1. Significantly, therapeutic inhibition of SPTBN1 blocks MASH and fibrosis in a human model. This study identifies SPTBN1 as a critical regulator of the functional phenotype of toxic aldehyde-induced MASH and a potential therapeutic Q2 target.

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Project description:MASLD, especially its severe form MASH, progresses to liver fibrosis, leading to cirrhosis and liver cancer. The crosstalk between spleen and liver in MASLD/MASH progression remains poorly understood. Here, we find the enlarged spleens in MASLD patients, and the induced TRNP1hiCD8+ T cells in the spleens of MASLD/MASH mouse models and confirmed in MASLD patients, with pro-fibrotic property by secreting INSR-α. Mechanistically, demethylated DNA and H3K27me3, increased H3K27ac, together with bolstered enhancer-promoter contact, synergistically reorganized chromatin topologically associating domains spatially to initiate the expression of transcription factor TRNP1 in splenic CD8+ T cells. TRNP1 then transcriptionally activates the expression of FURIN and CTSD, promoting the maturation and ectodomain shedding of INSR-α thereby facilitating its secretion to activate hepatic stellate cells. In vivo blockade of INSR-α using neutralizing antibodies alleviates MASLD/MASH-induced liver fibrosis. Therefore, this study reveals splenic TRNP1hiCD8+ T cells with pro-fibrotic property and suggests a potential anti-fibrotic strategy.

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