# Molecular mechanisms underlying the genetic association between PPP1R3B and hepatic steatosis

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $691,510

## Abstract

PROJECT SUMMARY
Non-alcoholic fatty liver disease (NAFLD) is a major public health issue that affects millions of Americans, and
that is increasing in prevalence with the global rise in obesity. Cutting edge human genetic approaches have
identified natural human genetic variants associated with liver fat. Of these, associations with two genes:
PNPLA3, and PPP1R3B, have been replicated in multiple studies. We have developed unique new mouse
models to help us understand how increased PPP1R3B protects against fatty liver. PPP1R3B encodes a
protein known to regulate liver glycogen, but which has only been connected to liver fat by genetic association:
in other words, the role of PPP1R3B in liver fat metabolism is unknown.
Interestingly, PPP1R3B is also genetically associated with multiple traits relevant to human metabolic health,
including fasting insulin and glucose, plasma lactate, alkaline phosphatase, and plasma cholesterol (total, LDL
and HDL cholesterol). All of these association signals map quite far from the end of the PPP1R3B gene, to a
long non-coding RNA (lncRNA) of unknown function, LOC157273. Despite the considerable physical distance,
genetic variants were found to correlate with increased liver PPP1R3B RNA. The minor allele (occurring in
~9% of Europeans) is associated with increased hepatic PPP1R3B mRNA expression and reduced liver and
plasma lipids. Our preliminary data in mice strongly suggest that PPP1R3B is the causal gene: liver-specific
PPP1R3B knockout mice (Ppp1r3bΔhep) have increased hepatic and plasma lipids, whereas increasing
Ppp1r3b levels in liver reduces hepatic and plasma lipids. We propose to elucidate the mechanisms by which
hepatic PPP1R3B influences hepatic fat and plasma cholesterol, and to determine how the natural variants
increase expression of the PPP1R3B gene.
!

## Key facts

- **NIH application ID:** 9985610
- **Project number:** 5R01DK114291-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Joseph A. Baur
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $691,510
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985610

## Citation

> US National Institutes of Health, RePORTER application 9985610, Molecular mechanisms underlying the genetic association between PPP1R3B and hepatic steatosis (5R01DK114291-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9985610. Licensed CC0.

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