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Single-cell RNA sequencing decipher hepatic injury and APOA4 as a biomarker in males with intrauterine growth restriction

ABSTRACT:

Intrauterine growth restriction (IUGR) is associated with increased relative liver weight at birth, hepatic function decline and a higher risk for chronic liver and cardiovascular diseases in adults. Precise mechanisms of early developmental plasticity to intervene in poor fetal programming and adult disease remain largely elusive and warrant extensive research. Selecting natural piglets’ model of IUGR, using the liver as a readout and combining previous transcriptome findings, a map of cellular landscape was created to reveal a sex-dependent manner in IUGR-induced hepatic injury and its long-term functional repercussions. At the one-week postnatal node, we reveal that in contrast to a converting trend about an immune-adapted phenotype in female IUGRs, the more severe hepatic injury in male IUGRs is attributed to persistent inflammation caused by abnormal lipid metabolism, which disrupts the interactions of non-immune cells, resulting in impaired liver regeneration lasting into adulthood. In addition, we consider APOA4 as a new biomarker for the detection of IUGRs and discover its underlying role in hypoxic conditions. Our study opens the possibility to early therapy and screening of gender-specific hepatic injury brought on by IUGR.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

SUBMITTER: yusen wei

PROVIDER: MTBLS6881 | MetaboLights | 2023-09-25

REPOSITORIES: MetaboLights

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Project description:Background & Aims: Rapid induction of beta-PDGF receptor (beta-PDGFR) is a core feature of hepatic stellate cell activation, the hallmark of liver fibrogenesis. However, biological consequences of the induction are not well characterized. We aimed to determine the involvement of beta-PDGFR-mediated molecular pathway activation on hepatic stellate cells in liver injury, fibrogenesis, and carcinogenesis in vivo. Methods: Loss and constitutive activation of beta-PDGFR were assessed in mouse models with either a stellate cell-specific beta-PDGFR knockout or the expression of an autoactivating mutation respectively. Liver injury and fibrosis were induced in two mechanistically distinct models: carbontetrachloride (CCl4) treatment and ligation of the common bile duct. Hepatocarcinogenesis with underlying liver injury/fibrosis was assessed by a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed isolated stellate cells from these models to determine deregulated pathways. Results: Depletion of beta-PDGFR in hepatic stellate cells led to decreased histological liver injury, serum transaminases, collagen alpha 1(I) and alpha smooth muscle actin expression, and collagen deposition. Stellate cell proliferation was significantly reduced after acute hepatic injury in vivo. In contrast, autoactivation of beta-PDGFR in stellate cells accelerated liver fibrosis, most prominently after 6 weeks of CCl4 induced injury. There was no difference in development of DEN-induced pre-neoplastic loci according to the status of beta-PDGFR. Conclusions: Depletion of beta-PDGFR in hepatic stellate cells attenuated the development of liver injury, fibrosis, and stellate cell proliferation in multiple animal models, whereas the constitutive activation of beta-PDGFR enhanced fibrosis. However, manipulation of beta-PDGFR alone did not reduce development of dysplastic nodules. These findings indicate that titration of receptor beta-PDGFR expression on stellate cells parallels fibrosis and injury, but may not impact the development of hepatic neoplasia alone. Hepatic stellate cells were isolated from liver of beta-PDGFR-wild-type or knockout mice, and treated with beta-PDGF ligand or vehicle control.

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Single-cell RNA sequencing decipher hepatic injury and APOA4 as a biomarker in males with intrauterine growth restriction

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