Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kα and PI3Kβ Activities and Is Promoted by RAS

Molinaro, Angela; Becattini, Barbara; Mazzoli, Arianna; Bleve, Augusto; Radici, Lucia; Maxvall, Ingela; Sopasakis, Victoria Rotter; Molinaro, Antonio; Bäckhed, Fredrik; Solinas, Giovanni

doi:10.1016/j.cmet.2019.03.010

Cited by 77 publications

(78 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Measurement of infection efficiency showed that 50 MOI of GFP adenovirus were sufficient to infect 100% of the three hepatoma cell lines we have investigated ( Supplementary Fig. S1), which is similar to what we have found in primary hepatocytes 7 . Furthermore, 100 MOI of H-RAS17N adenovirus overexpressed the H-RAS17N transgene to a similar extent in primary hepatocytes, HepG2, McARH7777, and Hepa1-6 ( Supplementary Fig.…”

Section: Mouse Hepa 1-6 and Rat Mcarh7777 Hepatoma Cells Also Displaysupporting

confidence: 84%

“…The procedures to generate, amplify, and titer the viral vectors used in this manuscript were previously described 7 . Brifely, the empty VmAdcDNA3 virusmid used to generate the recombinant adenoviral vectors and the control adenovirus expressing the green fluorescent protein were kindly gifted by Luciano Pirola at INSERM 1,060 CarMeN Lyon.…”

Section: Methodsmentioning

confidence: 99%

“…The dominant negative RAS mutant H-RAS17N completely blunts insulin driven MAPK signaling and partially reduces insulin-driven AKT phosphorylation in primary mouse and human hepatocytes 7 . To evaluate insulin signaling in HepG2 hepatoma cells we have measured insulin-induced receptor beta chain (IRβ) autophosphorylation, AKT phosphorylation, and ERK phosphorylation in HepG2 cells in parallel to primary mouse hepatocytes infected either with a control virus expressing the GFP or with a virus expressing the dominant negative mutant H-RAS17N ( Fig.…”

Section: Human Hepg2 Hepatoma Cells Display Aberrantly Activated Ras-mentioning

confidence: 96%

“…The metabolic function of the liver is highly integrated with other organs and insulin action on the hepatocyte implicates indirect mechanisms involving signals from adipocytes and the brain 4,6 . However, recent studies indicate that direct insulin action on the hepatocyte plays a dominant role in the control of glucose metabolism 7,8 . A better understanding of the direct insulin action on hepatocyte metabolism in physiological conditions and in obesity is therefore necessary to unravel the link between obesity, insulin resistance, and fatty liver disease.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Insulin signaling and glucose metabolism in different hepatoma cell lines deviate from hepatocyte physiology toward a convergent aberrant phenotype

Molinaro

Becattini

Solinas

2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

Hepatoma cell lines are widely used to model the hepatocyte for insulin signaling and fatty liver disease. However, a direct comparison of insulin action in primary hepatocytes and in hepatoma cell lines is needed to validate this model and to better understand liver cancer. Here we have investigated insulin signaling, gluconeogenic gene expression, glucose production, and fatty acid synthase abundance in primary hepatocytes and in HepG2, Hepa 1-6, and McARH7777 hepatoma cell lines. Differences in the electrophoretic profiles of protein extracts from human and mouse primary hepatocytes and the hepatoma cells lines are shown. Compared to primary hepatocytes, hepatoma cells showed high basal phosphorylation of AKT at Thr 308 and constitutively activated RAS-MAPK signaling, which were resistant to the dominant negative Ras mutant H-Ras17N. Hepatoma cell lines also showed defective expression of gluconeogenic enzymes, insulin unresponsive GSK phosphorylation, and marginal glucose production. Hepatoma cells also showed lower protein levels of fatty acid synthase and a largely distinct protein electrophoresis profile from hepatocytes but similar between different hepatoma lines. We conclude that hepatoma cell lines do not accurately model the hepatocyte for insulin action but may be valuable tools to investigate the proteomic changes conferring to hepatocellular carcinoma its peculiar metabolisms. Abbreviations Ras Retrovirus-associated DNA sequences MAPK Mitogen activated protein kinase PI3K Phosphoinositide 3 kinase GSK Glycogen synthase kinase G6P Glucose 6 phosphatase PEPCK Phosphoenolpyruvate carboxykinase FAS Fatty acid synthase Ser Serine Thr Threonine Obesity and type-2 diabetes have reached unprecedented proportions and may be the largest pandemic in the history of humanity 1. Furthermore, fatty liver disease is a condition closely associated with obesity and insulin resistance, which at advanced stage progresses to cirrhosis and hepatocellular carcinoma, and it was predicted that fatty liver disease will be the first cause for liver transplantation in the near future 2. The liver is a major insulin target organ, is the main source of endogenous glucose production, plays a chief role in the control of systemic lipid metabolism, and is central to the link between obesity and type-2 diabetes 3-5. Hence, identifying

show abstract

Section: Mouse Hepa 1-6 and Rat Mcarh7777 Hepatoma Cells Also Displaysupporting

confidence: 84%

Section: Methodsmentioning

confidence: 99%

Section: Human Hepg2 Hepatoma Cells Display Aberrantly Activated Ras-mentioning

confidence: 96%

mentioning

confidence: 99%

See 2 more Smart Citations

Insulin signaling and glucose metabolism in different hepatoma cell lines deviate from hepatocyte physiology toward a convergent aberrant phenotype

Molinaro

Becattini

Solinas

2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…Further transduction of insulin signaling occurs via phosphatidylinositol 3-kinase (PI3K)/AKT phosphorylation. AKT or Protein kinase B (PKB) are considered the main effectors of metabolic insulin actions ( Taniguchi et al, 2006 ; Molinaro et al, 2019 ). On the other hand, AKT1 and 3 are the leading players of mitogenic effects of insulin by RAS/mitogen activated protein kinase (MAPK) cascade and crosstalk with growth hormones ( Xu et al, 2006 ; Xu and Messina, 2009 ; Qiu et al, 2017 ).…”

Section: Overview Of Insulin Biosynthesis and Non-renal Action And Mementioning

confidence: 99%

Insulin: Trigger and Target of Renal Functions

Pina

Borges

Meneses

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Kidney function in metabolism is often underestimated. Although the word "clearance" is associated to "degradation", at nephron level, proper balance between what is truly degraded and what is redirected to de novo utilization is crucial for the maintenance of electrolytic and acid-basic balance and energy conservation. Insulin is probably one of the best examples of how diverse and heterogeneous kidney response can be. Kidney has a primary role in the degradation of insulin released in the bloodstream, but it is also incredibly susceptible to insulin action throughout the nephron. Fluctuations in insulin levels during fast and fed state add another layer of complexity in the understanding of kidney fine-tuning. This review aims at revisiting renal insulin actions and clearance and to address the association of kidney dysmetabolism with hyperinsulinemia and insulin resistance, both highly prevalent phenomena in modern society.

show abstract

Insulin Regulation of Hepatic Lipid Homeostasis

Uehara

Santoleri

Whitlock

et al. 2023

Comprehensive Physiology

View full text Add to dashboard Cite

The incidence of obesity, insulin resistance, and type II diabetes (T2DM) continues to rise worldwide. The liver is a central insulin-responsive metabolic organ that governs whole-body metabolic homeostasis. Therefore, defining the mechanisms underlying insulin action in the liver is essential to our understanding of the pathogenesis of insulin resistance. During periods of fasting, the liver catabolizes fatty acids and stored glycogen to meet the metabolic demands of the body. In postprandial conditions, insulin signals to the liver to store excess nutrients into triglycerides, cholesterol, and glycogen. In insulin-resistant states, such as T2DM, hepatic insulin signaling continues to promote lipid synthesis but fails to suppress glucose production, leading to hypertriglyceridemia and hyperglycemia. Insulin resistance is associated with the development of metabolic disorders such as cardiovascular and kidney disease, atherosclerosis, stroke, and cancer. Of note, nonalcoholic fatty liver disease (NAFLD), a spectrum of diseases encompassing fatty liver, inflammation, fibrosis, and cirrhosis, is linked to abnormalities in insulin-mediated lipid metabolism. Therefore, understanding the role of insulin signaling under normal and pathologic states may provide insights into preventative and therapeutic opportunities for the treatment of metabolic diseases. Here, we provide a review of the field of hepatic insulin signaling and lipid regulation, including providing historical context, detailed molecular mechanisms, and address gaps in our understanding of hepatic lipid regulation and the derangements under insulin-resistant conditions.

show abstract

Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kα and PI3Kβ Activities and Is Promoted by RAS

Cited by 77 publications

References 33 publications

Insulin signaling and glucose metabolism in different hepatoma cell lines deviate from hepatocyte physiology toward a convergent aberrant phenotype

Insulin signaling and glucose metabolism in different hepatoma cell lines deviate from hepatocyte physiology toward a convergent aberrant phenotype

Insulin: Trigger and Target of Renal Functions

Insulin Regulation of Hepatic Lipid Homeostasis

Contact Info

Product

Resources

About