mTOR Signaling in Growth Control and Disease

Cell, Journal Year: 2012, Volume and Issue: 149(2), P. 274 - 293

Published: April 1, 2012

Language: Английский

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Oxidative Stress and Diabetic Complications

Circulation Research, Journal Year: 2010, Volume and Issue: 107(9), P. 1058 - 1070

Published: Oct. 28, 2010

Oxidative stress plays a pivotal role in the development of diabetes complications, both microvascular and cardiovascular. The metabolic abnormalities cause mitochondrial superoxide overproduction endothelial cells large small vessels, as well myocardium. This increased production causes activation 5 major pathways involved pathogenesis complications: polyol pathway flux, formation AGEs (advanced glycation end products), expression receptor for its activating ligands, protein kinase C isoforms, overactivity hexosamine pathway. It also directly inactivates 2 critical antiatherosclerotic enzymes, nitric oxide synthase prostacyclin synthase. Through these pathways, intracellular reactive oxygen species (ROS) defective angiogenesis response to ischemia, activate number proinflammatory long-lasting epigenetic changes that drive persistent genes after glycemia is normalized (“hyperglycemic memory”). Atherosclerosis cardiomyopathy type are caused part by pathway-selective insulin resistance, which increases ROS from free fatty acids inactivation antiatherosclerosis enzymes ROS. Overexpression dismutase transgenic diabetic mice prevents retinopathy, nephropathy, cardiomyopathy. aim this review highlight advances understanding metabolite-generated complications.

Language: Английский

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Mechanisms of Insulin Action and Insulin Resistance

Physiological Reviews, Journal Year: 2018, Volume and Issue: 98(4), P. 2133 - 2223

Published: Aug. 1, 2018

The 1921 discovery of insulin was a Big Bang from which vast and expanding universe research into action resistance has issued. In the intervening century, some discoveries have matured, coalescing solid fertile ground for clinical application; others remain incompletely investigated scientifically controversial. Here, we attempt to synthesize this work guide further mechanistic investigation inform development novel therapies type 2 diabetes (T2D). rational such necessitates detailed knowledge one key pathophysiological processes involved in T2D: resistance. Understanding resistance, turn, requires normal action. review, both physiology pathophysiology are described, focusing on three target tissues: skeletal muscle, liver, white adipose tissue. We aim develop an integrated physiological perspective, placing intricate signaling effectors that carry out cell-autonomous response context tissue-specific functions generate coordinated organismal response. First, section II, effects direct, tissue reviewed, beginning at receptor working downstream. Section III considers critical underappreciated role crosstalk whole body action, especially essential interaction between lipolysis hepatic gluconeogenesis. is then described IV. Special attention given pathways become resistant setting chronic overnutrition, alternative explanation phenomenon ‟selective resistanceˮ presented. Sections V, VI, VII critically examine evidence against several putative mediators V reviews linking bioactive lipids diacylglycerol, ceramide, acylcarnitine resistance; VI impact nutrient stresses endoplasmic reticulum mitochondria discusses non-cell autonomous factors proposed induce including inflammatory mediators, branched-chain amino acids, adipokines, hepatokines. Finally, VIII, propose model links these final common metabolite-driven gluconeogenesis ectopic lipid accumulation.

Language: Английский

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Human Fatty Liver Disease: Old Questions and New Insights

Science, Journal Year: 2011, Volume and Issue: 332(6037), P. 1519 - 1523

Published: June 24, 2011

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem that affects one-third of adults and an increasing number children in developed countries. The begins with the aberrant accumulation triglyceride liver, which some individuals elicits inflammatory response can progress to cirrhosis cancer. Although NAFLD strongly associated obesity insulin resistance, its pathogenesis remains poorly understood, therapeutic options are limited. Here, we discuss recent mechanistic insights into NAFLD, focusing primarily on those have emerged from human genetic metabolic studies.

Language: Английский

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Energy Metabolism in the Liver

Comprehensive physiology, Journal Year: 2014, Volume and Issue: unknown, P. 177 - 197

Published: Jan. 10, 2014

The liver is an essential metabolic organ, and its function controlled by insulin other hormones. Glucose converted into pyruvate through glycolysis in the cytoplasm, subsequently oxidized mitochondria to generate ATP TCA cycle oxidative phosphorylation. In fed state, glycolytic products are used synthesize fatty acids de novo lipogenesis. Long-chain incorporated triacylglycerol, phospholipids, and/or cholesterol esters hepatocytes. These complex lipids stored lipid droplets membrane structures, or secreted circulation as very low-density lipoprotein particles. fasted secretes glucose both glycogenolysis gluconeogenesis. During pronged fasting, hepatic gluconeogenesis primary source for endogenous production. Fasting also promotes lipolysis adipose tissue, resulting release of nonesterified which ketone bodies though β-oxidation ketogenesis. Ketone provide a fuel extrahepatic tissues. Liver energy metabolism tightly regulated neuronal hormonal signals. sympathetic system stimulates, whereas parasympathetic suppresses, Insulin stimulates lipogenesis but suppresses gluconeogenesis, glucagon counteracts action. Numerous transcription factors coactivators, including CREB, FOXO1, ChREBP, SREBP, PGC-1α, CRTC2, control expression enzymes catalyze key steps pathways, thus controlling metabolism. Aberrant resistance, diabetes, nonalcoholic diseases. © 2014 American Physiological Society. Compr Physiol 4:177-197, 2014.

Language: Английский

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PI3K and cancer: lessons, challenges and opportunities

Nature Reviews Drug Discovery, Journal Year: 2014, Volume and Issue: 13(2), P. 140 - 156

Published: Jan. 31, 2014

Language: Английский

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AMPK Phosphorylates and Inhibits SREBP Activity to Attenuate Hepatic Steatosis and Atherosclerosis in Diet-Induced Insulin-Resistant Mice

Cell Metabolism, Journal Year: 2011, Volume and Issue: 13(4), P. 376 - 388

Published: April 1, 2011

Language: Английский

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Mechanisms and disease consequences of nonalcoholic fatty liver disease

Cell, Journal Year: 2021, Volume and Issue: 184(10), P. 2537 - 2564

Published: May 1, 2021

Language: Английский

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The PI3K/AKT pathway in obesity and type 2 diabetes

International Journal of Biological Sciences, Journal Year: 2018, Volume and Issue: 14(11), P. 1483 - 1496

Published: Jan. 1, 2018

Obesity and type 2 diabetes mellitus are complicated metabolic diseases that affect multiple organs characterized by hyperglycaemia.Currently, stable effective treatments for obesity not available.Therefore, the mechanisms leading to more ways treat should be identified.Based on accumulated evidences, PI3K/AKT signalling pathway is required normal metabolism due its characteristics, imbalance leads development of mellitus.This review focuses role in skeletal muscle, adipose tissue, liver, brain pancreas, discusses how this affects aforementioned diseases.We also summarize evidences recently identified therapeutic targets as mellitus.PI3K/AKT damaged various tissues body result insulin resistance, turn, resistance exacerbates pathway, forming a vicious circle.

Language: Английский

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Lipid metabolism in cancer

FEBS Journal, Journal Year: 2012, Volume and Issue: 279(15), P. 2610 - 2623

Published: May 23, 2012

Lipids form a diverse group of water‐insoluble molecules that include triacylglycerides, phosphoglycerides, sterols and sphingolipids. They play several important roles at cellular organismal levels. Fatty acids are the major building blocks for synthesis which mainly used energy storage. Phosphoglycerides, together with sphingolipids, represent structural components biological membranes. can also have in signalling, functioning as second messengers hormones. There is increasing evidence cancer cells show specific alterations different aspects lipid metabolism. These affect availability lipids membranes, degradation contribute to homeostasis abundance signalling functions. Changes metabolism numerous processes, including cell growth, proliferation, differentiation motility. This review will examine some been reported cancer, both levels, discuss how they tumourigenesis.

Language: Английский

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