Related Experiment Video

Updated: May 10, 2026

Measurement of Fatty Acid β-Oxidation in a Suspension of Freshly Isolated Mouse Hepatocytes
11:03

Measurement of Fatty Acid β-Oxidation in a Suspension of Freshly Isolated Mouse Hepatocytes

Published on: September 9, 2021

Fasting induces nuclear factor E2-related factor 2 and ATP-binding Cassette transporters via protein kinase A and

Supriya R Kulkarni1, Ajay C Donepudi, Jialin Xu

  • 11 Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island , Kingston, Rhode Island.

Antioxidants & Redox Signaling
|June 4, 2013
PubMed
Abstract

Insights

Fasting activates the NRF2-ARE pathway via cAMP/PKA and SIRT1, influencing ATP-binding Cassette (ABC) transporter expression. This study reveals nutrient status as a key regulator of NRF2 activity and the antioxidant response.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Biochemistry

Background:

  • ATP-binding Cassette (ABC) transporters (ABCC2-4) are crucial for chemical elimination and biliary excretion in hepatocytes.
  • Nuclear factor-E2 related-factor 2 (NRF2) typically mediates ABCC induction in response to chemical inducers or liver injury.
  • The role of NRF2 in regulating transporter expression during non-chemical liver perturbations remains largely undescribed.

Purpose of the Study:

  • To investigate whether cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) and Sirtuin-1 (SIRT1) signaling pathways modulate the expression of ABC transport proteins.
  • To explore the role of NRF2 in regulating transporter expression under non-chemical liver stress conditions, specifically fasting.

Main Methods:

  • Utilized fasting models in intact mice and primary mouse/human hepatocytes.
  • Administered 8-Bromoadenosine-cAMP (a cAMP analogue) and the PKA inhibitor H-89.
  • Examined NRF2 target gene expression, antioxidant response element (ARE) activity, and protein recruitment to promoter regions.
  • Employed liver-specific null mice for SIRT1 and NRF2.

Main Results:

  • Fasting significantly increased NRF2 target gene expression (1.5-5 fold) in mouse liver through NRF2- and SIRT1-dependent pathways.
  • cAMP analogue treatment elevated NRF2 target gene expression and ARE activity in hepatocytes, an effect diminished by PKA inhibition.
  • Fasting-induced NRF2 target gene expression was reduced in hepatocytes and livers from SIRT1 and NRF2 knockout mice.
  • NRF2 and SIRT1 were observed to bind to MAREs and AREs in the human ABCC2 promoter.

Conclusions:

  • Nutrient status, specifically fasting, plays a novel role in regulating NRF2 activity and the cellular antioxidant response.
  • The cAMP/PKA and SIRT1 pathways act as upstream regulators for fasting-induced activation of the NRF2-ARE pathway.
  • These findings highlight a new mechanism for controlling ABC transporter expression independent of chemical induction.

More Related Videos

Assessment of the Metabolic Effects of Isocaloric 2:1 Intermittent Fasting in Mice08:06

Assessment of the Metabolic Effects of Isocaloric 2:1 Intermittent Fasting in Mice

Published on: November 27, 2019

Related Concept Videos

Metabolic States of the Body: Fasting and Starvation01:24

Metabolic States of the Body: Fasting and Starvation

During the initial hours of fasting, the body uses up its glycogen stores as an energy source. Once these glycogen reserves are depleted, the body begins breaking down stored triglycerides and structural proteins. During this stage, glycerol becomes a key substrate for gluconeogenesis, while free fatty acids undergo beta-oxidation to provide energy for tissues, such as skeletal muscle. In the fasting state, the body spares protein breakdown as much as possible to conserve muscle and structural...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
Regulation of Nuclear Protein Sorting01:45

Regulation of Nuclear Protein Sorting

Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
Metabolic States of the Body: The Postabsorptive State01:18

Metabolic States of the Body: The Postabsorptive State

The postabsorptive state usually starts about four hours after a meal and lasts until the next meal is eaten. During this time, the digestive system stops absorbing nutrients, and the body uses stored energy reserves to maintain stable blood glucose levels.
Initially, glycogen stored in the liver is broken down to release glucose into the bloodstream, while glycogen in the muscles is broken down to supply glucose for energy directly within the muscle cells. As glycogen stores diminish,...
cAMP-dependent Protein Kinase Pathways01:25

cAMP-dependent Protein Kinase Pathways

Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...