Plasma membrane (PM) free cholesterol (FC) is emerging as an important modulator of signal transduction. Here, we show that hepatocyte-specific knockout (HSKO) of the cellular FC exporter, ATP-binding cassette transporter A1 (ABCA1), leads to decreased PM FC content and defective trafficking of lysosomal FC to the PM. Compared with controls, chow-fed HSKO mice had reduced hepatic (1) insulin-stimulated Akt phosphorylation, (2) activation of the lipogenic transcription factor Sterol Regulatory Element Binding Protein (SREBP)-1c, and (3) lipogenic gene expression. Consequently, Western-type diet-fed HSKO mice were protected from steatosis. Surprisingly, HSKO mice had intact glucose metabolism; they showed normal gluconeogenic gene suppression in response to re-feeding and normal glucose and insulin tolerance. We conclude that: (1) ABCA1 maintains optimal hepatocyte PM FC, through intracellular FC trafficking, for efficient insulin signaling; and (2) hepatocyte ABCA1 deletion produces a form of selective insulin resistance so that lipogenesis is suppressed but glucose metabolism remains normal.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512440 | PMC |
| http://dx.doi.org/10.1016/j.celrep.2017.05.032 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Membrane-bound -acyltransferase 7 (MBOAT7) shapes lysosomal lipid homeostasis and function to control alcohol-associated liver injury.
Elife
April 2024
Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United States.
Recent genome-wide association studies (GWAS) have identified a link between single-nucleotide polymorphisms (SNPs) near the MBOAT7 gene and advanced liver diseases. Specifically, the common MBOAT7 variant (rs641738) associated with reduced MBOAT7 expression is implicated in non-alcoholic fatty liver disease (NAFLD), alcohol-associated liver disease (ALD), and liver fibrosis. However, the precise mechanism underlying MBOAT7-driven liver disease progression remains elusive.
View Article and Find Full Text PDFArticle Synopsis
- Recent genome-wide association studies have linked specific SNPs near the MBOAT7 gene to increased risk for advanced liver diseases like NAFLD and ALD, especially in people with chronic hepatitis infections.
- The MBOAT7 gene is crucial for producing a specific lipid, and a common variant (rs641738) lowers its expression, which exacerbates liver disease progression.
- Research shows that deleting MBOAT7 in liver cells leads to more severe alcohol-induced liver damage, highlighting how alterations in lipid metabolism can affect liver health in heavy drinkers.
Hepatocyte ABCA1 deficiency is associated with reduced HDL sphingolipids.
Front Physiol
August 2023
Institute of Clinical Chemistry, University Hospital Zurich and University Zurich, Zurich, Switzerland.
ATP binding cassette transporter A1 (ABCA1) limits the formation of high density lipoproteins (HDL) as genetic loss of ABCA1 function causes virtual HDL deficiency in patients with Tangier disease. Mice with a hepatocyte-specific ABCA1 knockout (Abca1 HSKO) have 20% of wild type (WT) plasma HDL-cholesterol levels, suggesting a major contribution of hepatic ABCA1 to the HDL phenotype. Whether plasma sphingolipids are reduced in Tangier disease and to what extent hepatic ABCA1 contributes to plasma sphingolipid (SL) levels is unknown.
View Article and Find Full Text PDFTargeted Deletion of Hepatocyte Abca1 Increases Plasma HDL (High-Density Lipoprotein) Reverse Cholesterol Transport via the LDL (Low-Density Lipoprotein) Receptor.
Arterioscler Thromb Vasc Biol
September 2019
From the Department of Internal Medicine, Section of Molecular Medicine (A.C.B., M.L., C-C.C.K., E.B., X.W., J.K.S., J.S.P.), Wake Forest School of Medicine, Winston-Salem, NC.
Objective: The role of hepatocyte Abca1 (ATP binding cassette transporter A1) in trafficking hepatic free cholesterol (FC) into plasma versus bile for reverse cholesterol transport (RCT) is poorly understood. We hypothesized that hepatocyte Abca1 recycles plasma HDL-C (high-density lipoprotein cholesterol) taken up by the liver back into plasma, maintaining the plasma HDL-C pool, and decreasing HDL-mediated RCT into feces. Approach and Results: Chow-fed hepatocyte-specific Abca1 knockout (HSKO) and control mice were injected with human HDL radiolabeled with I-tyramine cellobiose (I-TC; protein) and H-cholesteryl oleate (H-CO).
View Article and Find Full Text PDFHepatic ABCA1 deficiency is associated with delayed apolipoprotein B secretory trafficking and augmented VLDL triglyceride secretion.
Biochim Biophys Acta Mol Cell Biol Lipids
October 2017
Department of Internal Medicine-Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
ATP binding cassette transporter A1 (ABCA1) is a membrane transporter that facilitates nascent HDL formation. Tangier disease subjects with complete ABCA1 deficiency have <5% of normal levels of plasma HDL, elevated triglycerides (TGs), and defective vesicular trafficking in fibroblasts and macrophages. Hepatocyte-specific ABCA1 knockout mice (HSKO) have a similar lipid phenotype with 20% of normal plasma HDL levels and a two-fold elevation of plasma TGs due to hepatic overproduction of large, triglyceride-enriched VLDL.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!