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Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2021)

The Hybrid Mouse Diversity Panel (HMDP) is a systems genetic resource of over one hundred different mouse strains. The genetic variation and subsequent phenotypic variation between strains in the HMDP encompass a spectrum of metabolic phenotypes from weight gain following a high-fat diet to susceptibility to heart and liver disease. My dissertation research focuses on the analysis of genetic and genomic data originating from multiple HMDP studies for Metabolic Syndrome phenotypes. Firstly, I identified DNA methylation patterns associated with diet-induced obesity that were observed across diverse genetic backgrounds. I then asked whether these epigenetic changes were maintained following weight loss in a subset of strains. Secondly, I characterized novel genes for atherosclerosis, Nnmt, Csf1, and Zhx2. Lastly, I used transcriptional approaches with genetically diverse mouse strains to identify susceptibility mechanisms involved in the development of progressive liver disease phenotypes. Taken together, this body of research encompasses genetic, cell-type, gene expression, and epigenetic approaches to investigate mechanisms involved in obesity, heart, and liver disease.

    Cover page: Leveraging variation in genetically diverse mouse strains to study Metabolic Syndrome phenotypes
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2023)

    Background & aims

    Nonalcoholic steatohepatitis (NASH) is a complex disease involving both genetic and environmental factors in its onset and progression. We analyzed NASH phenotypes in a genetically diverse cohort of mice, the Hybrid Mouse Diversity Panel, to identify genes contributing to disease susceptibility.

    Methods

    A "systems genetics" approach, involving integration of genetic, transcriptomic, and phenotypic data, was used to identify candidate genes and pathways in a mouse model of NASH. The causal role of Matrix Gla Protein (MGP) was validated using heterozygous MGP knockout (Mgp+/-) mice. The mechanistic role of MGP in transforming growth factor-beta (TGF-β) signaling was examined in the LX-2 stellate cell line by using a loss of function approach.

    Results

    Local cis-acting regulation of MGP was correlated with fibrosis, suggesting a causal role in NASH, and this was validated using loss of function experiments in 2 models of diet-induced NASH. Using single-cell RNA sequencing, Mgp was found to be primarily expressed in hepatic stellate cells and dendritic cells in mice. Knockdown of MGP expression in stellate LX-2 cells led to a blunted response to TGF-β stimulation. This was associated with reduced regulatory SMAD phosphorylation and TGF-β receptor ALK1 expression as well as increased expression of inhibitory SMAD6. Hepatic MGP expression was found to be significantly correlated with the severity of fibrosis in livers of patients with NASH, suggesting relevance to human disease.

    Conclusions

    MGP regulates liver fibrosis and TGF-β signaling in hepatic stellate cells and contributes to NASH pathogenesis.
      Cover page: Role of Matrix Gla Protein in Transforming Growth Factor-β Signaling and Nonalcoholic Steatohepatitis in Mice
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