Related Experiment Video

Updated: Sep 10, 2025

Measurement of Insulin- and Contraction-Stimulated Glucose Uptake in Isolated and Incubated Mature Skeletal Muscle from Mice
08:01

Measurement of Insulin- and Contraction-Stimulated Glucose Uptake in Isolated and Incubated Mature Skeletal Muscle from Mice

Published on: May 16, 2021

6.0K

ATP8B1 Deficiency Causes Phosphodiesterase 4-Mediated Glucagon Resistance and Impaired Gluconeogenesis in Mouse and

Jung-Chin Chang1,2, Wietse In Het Panhuis2,3, Shu-Hao Hsu4

  • 1Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.

Liver International : Official Journal of the International Association for the Study of the Liver
|August 25, 2025
PubMed

Insights

ATP8B1 deficiency in progressive familial intrahepatic cholestasis type I (PFIC1) leads to impaired liver glucose regulation by upregulating PDE4D, causing glucagon resistance. This impacts gluconeogenesis and glycogenolysis in both mouse models and PFIC1 patients.

Area of Science:

  • Hepatology
  • Metabolic Research
  • Genetics

Background:

  • ATP8B1 deficiency causes progressive familial intrahepatic cholestasis type I (PFIC1).
  • PFIC1 patients may exhibit metabolic dysregulation beyond cholestasis, including glucose and lipid metabolism.
  • ATP8B1's role in hepatic glucose and lipid metabolism requires further investigation.

Purpose of the Study:

  • To investigate the role of ATP8B1 in hepatic glucose and lipid metabolism.
  • To utilize the Atp8b1G308V/G308V mutant mouse as a preclinical model for PFIC1 metabolic studies.
  • To validate findings in PFIC1 patient liver samples.

Main Methods:

  • Examined Atp8b1G308V/G308V and wild-type mice.
  • Assessed hepatic glucose metabolism via oral glucose tolerance tests and plasma glucose/insulin/lipid quantification.
  • Conducted mechanistic studies in primary mouse hepatocytes and HepG2 cells, validating with PFIC1 patient liver tissues.

Main Results:

  • Atp8b1G308V/G308V mice displayed reduced fasting glucose, triglycerides, and insulin, suggesting impaired glucagon response.
  • Primary mouse hepatocytes showed reduced glucagon signaling and increased Pde4 isoforms; PDE4 inhibition normalized signaling.
  • PFIC1 patient livers exhibited elevated PDE4D, reduced p-CREB, and low glycogen content.

Conclusions:

  • ATP8B1 deficiency upregulates hepatic PDE4D in both mouse models and PFIC1 patients.
  • PDE4D-mediated glucagon resistance contributes to impaired gluconeogenesis and altered glycogenolysis.
  • This study provides novel metabolic insights into ATP8B1 deficiency in PFIC1.
Abstract

Keywords:
cholestasiscyclic adenosine monophosphategluconeogenesisglucose

More Related Videos

Hyperinsulinemic-euglycemic Clamps in Conscious, Unrestrained Mice11:10

Hyperinsulinemic-euglycemic Clamps in Conscious, Unrestrained Mice

Published on: November 16, 2011

94.7K
Phosphorus-31 Magnetic Resonance Spectroscopy: A Tool for Measuring In Vivo Mitochondrial Oxidative Phosphorylation Capacity in Human Skeletal Muscle09:40

Phosphorus-31 Magnetic Resonance Spectroscopy: A Tool for Measuring In Vivo Mitochondrial Oxidative Phosphorylation Capacity in Human Skeletal Muscle

Published on: January 19, 2017

11.8K

Related Concept Videos

Inborn Errors of Metabolism01:20

Inborn Errors of Metabolism

Phenylketonuria (PKU) is a protein metabolism disorder characterized by high blood levels of the amino acid phenylalanine. This results from a mutation in the gene responsible for phenylalanine hydroxylase, an enzyme that converts phenylalanine into tyrosine. When this enzyme is deficient, phenylalanine builds up in the blood, leading to symptoms such as vomiting, rashes, seizures, growth deficiency, and severe mental retardation. An early diagnosis and a diet restricting phenylalanine intake...
241
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,...
6.6K
Glucose Transporters01:27

Glucose Transporters

Glucose transporters facilitate the transport of glucose across the cell membrane. In addition to glucose, some glucose transporters can also aid the movement of other hexoses such as fructose, mannose, and galactose.
Facilitated diffusion-glucose transporters (GLUTs) are encoded by the solute-linked carrier (SLC) family 2, subfamily A gene family, or SLC2A. The 14 GLUT protein members are distributed into three classes:
24.1K
Glucose Homeostasis: Pancreatic Islets and Insulin Secretion01:27

Glucose Homeostasis: Pancreatic Islets and Insulin Secretion

The pancreatic islets comprising only 1%-2% of the volume are highly vascularized and innervated mini-organs. They contain five endocrine cell types, including β cells that secrete insulin, which is synthesized as a single polypeptide chain, preproinsulin, processed to proinsulin, and finally to insulin and C-peptide. This process is complex and regulated, involving the Golgi complex, the endoplasmic reticulum, and the secretory granules of the β cell.
Insulin and C-peptide are...
1.4K
Cell Specific Gene Expression01:58

Cell Specific Gene Expression

Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
13.9K
ATP Synthase: Mechanism01:48

ATP Synthase: Mechanism

In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
15.1K