# Balance between HNF4a isoforms in the carbohydrate-lipid metabolic switch

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2023 · $409,162

## Abstract

Abstract
 Hepatocyte Nuclear Factor 4α (HNF4α), a master regulator of liver-specific gene expression, is regulated by
two promoters (P1 and P2) which drive expression of two groups of HNF4α isoforms referred to as HNF4α1
and HNF4α7. HNF4α is a known regulator of gluconeogenesis and mutated in maturity onset diabetes of the
young one (MODY1). Conventionally, it was thought that HNF4α1, but not HNF4α7, is expressed in the normal
adult liver, while HNF4α1 is downregulated and HNF4α7 is upregulated in liver cancer. Now, research in our lab
reveals a previously undescribed role for HNF4α7 in the normal adult mouse liver – one involved in the diurnal
variations of lipid and carbohydrate metabolism. More specifically, HNF4α1 appears to be a major driver of
gluconeogenesis while HNF4α7 is a driver of ketogenesis: we propose that alterations in the levels of the HNF4α
isoforms during the day flip the molecular switch between the two. Our preliminary data also show that HNF4α7
is required for increased levels of circulating ketone bodies in female mice. AMP-Activated Protein Kinase
(AMPK), an energy-sensing enzyme, has been shown to phosphorylate HNF4α1 in vitro, but effects in vivo and
on HNF4α7 are not known. SIRT1 is a deacetylase that works with AMPK to regulate glucose and lipid
metabolism. HNF4α1 is known to be acetylated and our preliminary data suggest that HNF4α7 but not HNF4α1
interacts with SIRT1. Here, we propose to use HNF4α1-expressing (α1HMZ) and HNF4α7-expressing exon
swap mice (α7HMZ) to determine the physiological function of the HNF4α isoforms in the switch between
gluconeogenesis and ketogenesis, and to characterize the impact of sex on those functions. In Aim 1, we will
determine whether intermittent fasting and a ketogenic diet increase the levels of HNF4α7 in the liver, and
whether the increase occurs in all hepatocytes, or just a subset. We will determine the consequences of HNF4α7
on gene expression. Kidney and intestines will also be explored. In Aim 2, we will determine whether the AMPK
pathway acts in a differential fashion on the HNF4α isoforms to help flip the metabolic switch. Phosphorylation
by AMPK and deacetylation by SIRT1 will be explored. Finally, in Aim 3, we will determine whether the estrogen
pathway impacts the HNF4α isoforms in female mice and determine the consequences for the metabolic switch.
 Our compelling preliminary data that the HNF4α isoforms are involved in the switch between
gluconeogenesis and ketogenesis shed new light on this basic metabolic process that occurs on a daily basis
and under conditions of feeding and fasting. The results from this proposal will illuminate not only the molecular
mechanism underlying the switch but also how that mechanism is impacted by sex. The proposed studies have
the potential to impact our understanding of numerous metabolic diseases, including diabetes, obesity, fatty liver
disease and cancer. Finally, given the fact that ketone bodies serve as a source of fuel for th...

## Key facts

- **NIH application ID:** 10663333
- **Project number:** 5R01DK127082-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** FRANCES M. SLADEK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $409,162
- **Award type:** 5
- **Project period:** 2021-09-25 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10663333

## Citation

> US National Institutes of Health, RePORTER application 10663333, Balance between HNF4a isoforms in the carbohydrate-lipid metabolic switch (5R01DK127082-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10663333. Licensed CC0.

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