# Bile Acids and Sphingosine 1-Phosphate in Non-Alcoholic Steatohepatitis (NASH)

> **NIH VA I01** · VA VETERANS ADMINISTRATION HOSPITAL · 2024 · —

## Abstract

Non-alcoholic fatty liver disease (NAFLD) is becoming a globally prevalent disease, especially among US
veterans. NAFLD and non-alcoholic steatohepatitis (NASH) are recognized as hepatic manifestations of
metabolic syndrome. The disease progression from simple steatosis to NASH, fibrosis, cirrhosis, and
hepatocellular carcinoma (HCC) is promoted by multiple-hit instead of two-hit, including disruption of intrahepatic
bile acid (BA) homeostasis, aberrant activation of the innate immune response, insulin resistance, dyslipidemia,
and dysbiosis. Although much new information on the pathogenesis of NAFLD/NASH has been gained during
the last decade, no effective therapy has been developed due to the incomplete understanding of the
pathogenesis of this complex disease. Considering the rapid increase in the incidence and prevalence worldwide
of fatty liver diseases, the development of new therapeutic interventions for NAFLD is especially urgent and is
the long-term objective of this application. BAs are important signaling molecules involved in regulating lipid,
glucose, and energy metabolism by activating nuclear receptors and G protein-coupled receptors (GPCRs), such
as farnesoid X receptor (FXR), TGR5, and sphingosine-1 phosphate receptor 2 (S1PR2). We have reported that
conjugated primary BAs activate the AKT and ERK1/2 pathways via Gαi protein-coupled S1PR2. It also has
been reported that phosphorylation of sphingosine kinase 2 (SphK2) by ERK1/2 increases nuclear sphingosine-
1 phosphate (S1P) levels. Nuclear S1P is a potent endogenous inhibitor of specific histone deacetylase 1 &2
(HDAC1 and 2). Inhibition of HDAC1 has been reported to reduce hepatic lipid accumulation. BAs are also
important modulators of innate immunity. Our previous studies reported that deletion of S1PR2 or SphK2 in
hepatocytes significantly increased lipid accumulation. Both S1PR2-/- and SphK2-/- mice are more prone to
western diet (WD)-induced hepatic steatosis and inflammation. In the liver, both S1PR2 and SphK2 are highly
expressed in hepatocytes, macrophages, and cholangiocytes. A recent study reported that SphK2-generated
S1P activated an anti-inflammatory response by suppressing the stimulator of type 1 interferon gene (STING)
signaling in macrophages. It has also been reported that hepatic STING expression is upregulated in NASH
patients and activation of STING in macrophages contributes to NASH disease progression. Our preliminary
data further indicate that serum BA composition and levels were significantly changed in a diet-induced mouse
NASH model, which was similar to the finding in human NASH patients. Furthermore, the expression of SphK2
was significantly down-regulated, but the expression of STING was upregulated in the livers of human NASH
patients and the NASH mouse model. Therefore we HYPOTHESIZE that BA-mediated activation of
S1PR2/SphK2 is pivotal in the maintenance of hepatic lipid homeostasis and modulation of innate
immune response under metabolic stress...

## Key facts

- **NIH application ID:** 10721340
- **Project number:** 5I01BX005730-02
- **Recipient organization:** VA VETERANS ADMINISTRATION HOSPITAL
- **Principal Investigator:** HUIPING ZHOU
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10721340

## Citation

> US National Institutes of Health, RePORTER application 10721340, Bile Acids and Sphingosine 1-Phosphate in Non-Alcoholic Steatohepatitis (NASH) (5I01BX005730-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10721340. Licensed CC0.

---

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