# Systems Genetics Dissection of Non-alcoholic Steatohepatitis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $667,747

## Abstract

PROJECT SUMMARY
Non-alcoholic fatty liver disease (NAFLD) is a common but poorly understood disease with a critical need for
improved diagnosis and treatment. It is the most common form of chronic liver disease manifested as a spectrum
of hepatic abnormalities ranging from simple steatosis, steatohepatitis (NASH) to fibrosis and cirrhosis in the
absence of excessive alcohol consumption. During the present grant cycle, we have used an approach termed
“systems genetics” to identify genetic and environmental interactions in NAFLD. Using omics technologies, we
directly examined the effects of genetic variation on molecular phenotypes, such as global transcript, protein, or
metabolite levels. This enables the identification of causal genes and pathways and the modeling of higher order
interactions in the disease process. We validated two key driver genes, matrix gla protein (Mgp) and insulin-like
growth factor binding protein 4 (Igfbp4) as causal genes in vivo by showing that experimental modulation of their
expression led to significant reduction in liver fibrosis in mice. In Aim 1a, we will examine the role of Mgp in
hepatic stellate cells (HSC) physiology by using HSC-specific knockout mice. In Aim 1b, we will use the Four
Core Genotypes mouse model to dissect the respective role of gonadal hormones and sex-chromosomes in
conferring sex-specific protection of NASH in the Mgp knockout mice. In Aim 1c, we will investigate the
mechanisms by which Igfbp4 alters NASH using inducible overexpression and knockout mice. Additionally, its
role in TGF-β and SMAD pathways will be examined. Our single-cell transcriptome analysis revealed potential
cell-cell interactions important for liver fibrosis. We observed significant information flow from various liver cell
types to HSC during the onset of liver fibrosis. In Aim 2a, we will examine the role of these interactions in HSC
function using primary HSC. In Aim 2b, we will examine intercellular communication between HSC and other
liver cell types by 3D liver spheroid culture. Plasma metabolomic analysis showed that circulating indole-3-
propionic acid (IPA) levels were lower in NASH patients with liver fibrosis and that IPA levels were significantly
correlated with liver transcripts enriched in HSC activation and hepatic fibrosis signaling. The links among IPA,
cellular NAD+ levels and gut microbiota will be the focus for investigation in Aim 3. IPA will be supplemented in
mice to test the hypothesis that IPA protects the liver from NASH by increasing NAD+ levels in hepatocytes (Aim
3a). We will use knockout mice of two NAD+ catabolizing enzymes, namely nicotinamide N-methyl transferase
(NNMT) and CD38, to examine the link between NAD+ levels and NASH (Aim 3b). To test the causal links
between gut bacterial IPA production and host phenotypes, we will perform gnotobiotic studies with germ-free
mice. The hypothesis that perturbating IPA levels through transplantation of genetically engineered bacteria into
germ-fre...

## Key facts

- **NIH application ID:** 10881552
- **Project number:** 2R01DK117850-05A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Aldons Jake Lusis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $667,747
- **Award type:** 2
- **Project period:** 2019-07-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881552

## Citation

> US National Institutes of Health, RePORTER application 10881552, Systems Genetics Dissection of Non-alcoholic Steatohepatitis (2R01DK117850-05A1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10881552. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*