High-fat diet induced alterations in plasma membrane cholesterol content impairs insulin receptor binding and signalling in mouse liver but is ameliorated by atorvastatin

Sabapathy, Thiru; Helmerhorst, Erik; Ellison, Gaewyn; Bridgeman, Stephanie Claire; Mamotte, Cyril

doi:10.1016/j.bbadis.2022.166372

Cited by 5 publications

(3 citation statements)

References 43 publications

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“…We have not directly addressed the molecular mechanism driving the increased basal phosphorylation of MET, but hypothesize that the diet-induced changes in the bilipid layer of the hepatocytes may alter the affinity and the dimerization rate of MET rendering the receptor a central integrator of metabolic changes. In support of this hypothesis, it has been reported that a high fat diet decreased the cholesterol content of the plasma membrane of hepatocytes and reduced the affinity of the insulin receptor to insulin (Sabapathy et al, 2022). In line with this report, our analysis of canonical pathways showed that cholesterol biosynthesis was downregulated in WD-derived hepatocytes.…”

Section: Discussionsupporting

confidence: 90%

Basal MET Phosphorylation is an Indicator of Hepatocyte Dysregulation in Liver Disease

Burbano de Lara,

Kemmer,

Biermayer

et al. 2023

Preprint

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Chronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, Non-alcoholic fatty liver disease (NAFLD) is gaining importance as the disease can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in NAFLD development, but molecular mechanisms responsible for disease progression remained unresolved. Here, we uncover in primary hepatocytes from a preclinical model fed with a Western diet (WD) a strong downregulation of the PI3K-AKT pathway and an upregulation of the MAPK pathway. Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveal patient-specific variability in basal MET phosphorylation, which correlates with patient outcome after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.

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Section: Discussionsupporting

confidence: 90%

Basal MET Phosphorylation is an Indicator of Hepatocyte Dysregulation in Liver Disease

Burbano de Lara,

Kemmer,

Biermayer

et al. 2023

Preprint

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“…We have not directly addressed the molecular mechanism driving the increased basal phosphorylation of MET, but hypothesize that the diet-induced changes in the cell surface membrane of hepatocytes may alter the dimerization rate of MET receptors and change the heterodimerization capabilities of MET rendering the receptor a central integrator of metabolic changes. In support of this hypothesis, it has been reported that a high fat diet decreased the cholesterol content of the plasma membrane of hepatocytes and reduced the affinity of the insulin receptor to insulin (Sabapathy et al, 2022 ). In line with this report, our analysis of canonical pathways showed that cholesterol biosynthesis was downregulated in WD-derived hepatocytes.…”

Section: Discussionmentioning

confidence: 85%

Basal MET phosphorylation is an indicator of hepatocyte dysregulation in liver disease

Burbano de Lara,

Kemmer,

Biermayer

et al. 2024

Mol Syst Biol

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Chronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, metabolic dysfunction-associated steatotic liver disease (MASLD) is gaining importance as the disease can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in MASLD development, but molecular mechanisms responsible for disease progression remained unresolved. Here, we uncover in primary hepatocytes from a preclinical model fed with a Western diet (WD) an increased basal MET phosphorylation and a strong downregulation of the PI3K-AKT pathway. Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveal patient-specific variability in basal MET phosphorylation, which correlates with patient outcome after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.

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“…Dietary polyunsaturated fatty acids are essential to human health, they play important roles in both membrane phospholipid composition, which increases plasma membrane fluidity, and provide the backbone to several signalling lipids (Baccouch et al, 2023). The ability of receptors to move within the cellular plasma membrane and into intracellular compartments is vital to regulate their function (Fang et al, 2020) and an individual's cellular membrane composition may be altered because of diet, medications and genetic factors (Sabapathy et al, 2022). For example, mice fed a high-fat diet for 21 days have both lipid and protein compositional changes in cellular plasma membranes that result in an impaired capacity for oxidative phosphorylation, increased reactive oxygen species (ROS) production, hepatosteatosis and insulin resistance (Kahle et al, 2015).…”

Section: Membrane Composition and Incretin Receptor Actionmentioning

confidence: 99%

Variation in responses to incretin therapy: Modifiable and non-modifiable factors

Austin

Tomás

2023

Front. Mol. Biosci.

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Type 2 diabetes (T2D) and obesity have reached epidemic proportions. Incretin therapy is the second line of treatment for T2D, improving both blood glucose regulation and weight loss. Glucagon-like peptide-1 (GLP-1) and glucose-stimulated insulinotropic polypeptide (GIP) are the incretin hormones that provide the foundations for these drugs. While these therapies have been highly effective for some, the results are variable. Incretin therapies target the class B G protein-coupled receptors GLP-1R and GIPR, expressed mainly in the pancreas and the hypothalamus, while some therapeutical approaches include additional targeting of the related glucagon receptor (GCGR) in the liver. The proper functioning of these receptors is crucial for incretin therapy success and here we review several mechanisms at the cellular and molecular level that influence an individual’s response to incretin therapy.

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High-fat diet induced alterations in plasma membrane cholesterol content impairs insulin receptor binding and signalling in mouse liver but is ameliorated by atorvastatin

Cited by 5 publications

References 43 publications

Basal MET Phosphorylation is an Indicator of Hepatocyte Dysregulation in Liver Disease

Basal MET Phosphorylation is an Indicator of Hepatocyte Dysregulation in Liver Disease

Basal MET phosphorylation is an indicator of hepatocyte dysregulation in liver disease

Variation in responses to incretin therapy: Modifiable and non-modifiable factors

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