scholarly journals Mitochondrial stress protein HSP60 regulates ER stress-induced hepatic lipogenesis

2020 ◽  
Vol 64 (2) ◽  
pp. 67-75 ◽  
Author(s):  
Ting Xiao ◽  
Xiuci Liang ◽  
Hailan Liu ◽  
Feng Zhang ◽  
Wen Meng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Hepatic Steatosis ◽  
Molecular Mechanisms ◽  
Stress Protein ◽  
Hepatic Lipogenesis ◽  
Mitochondrial Stress ◽  
Hsp60 Expression ◽  
Mouse Hepatocytes

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are associated with hepatic steatosis and insulin resistance. Molecular mechanisms underlying ER stress and/or mitochondrial dysfunction that cause metabolic disorders and hepatic steatosis remain to be fully understood. Here, we found that a high fat diet (HFD) or chemically induced ER stress can stimulate mitochondrial stress protein HSP60 expression, impair mitochondrial respiration, and decrease mitochondrial membrane potential in mouse hepatocytes. HSP60 overexpression promotes ER stress and hepatic lipogenic protein expression and impairs insulin signaling in mouse hepatocytes. Mechanistically, HSP60 regulates ER stress-induced hepatic lipogenesis via the mTORC1-SREBP1 signaling pathway. These results suggest that HSP60 is an important ER and mitochondrial stress cross-talking protein and may control ER stress-induced hepatic lipogenesis and insulin resistance.

scholarly journals Aberrant Hepatic Expression of PPARγ2 Stimulates Hepatic Lipogenesis in a Mouse Model of Obesity, Insulin Resistance, Dyslipidemia, and Hepatic Steatosis

2006 ◽  
Vol 281 (49) ◽  
pp. 37603-37615 ◽  
Author(s):  
Yuan-Li Zhang ◽  
Antonio Hernandez-Ono ◽  
Patty Siri ◽  
Stuart Weisberg ◽  
Donna Conlon ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Mouse Model ◽  
Hepatic Steatosis ◽  
Hepatic Lipogenesis ◽  
Hepatic Expression

scholarly journals Relationship Between Oxidative Stress, ER Stress, and Inflammation in Type 2 Diabetes: The Battle Continues

2019 ◽  
Vol 8 (9) ◽  
pp. 1385 ◽  
Author(s):  
Burgos-Morón ◽  
Abad-Jiménez ◽  
Marañón ◽  
Iannantuoni ◽  
Escribano-López ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Current Knowledge ◽  
Β Cells ◽  
The Relationship ◽  
And Oxidative Stress

Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia and insulin resistance in which oxidative stress is thought to be a primary cause. Considering that mitochondria are the main source of ROS, we have set out to provide a general overview on how oxidative stress is generated and related to T2D. Enhanced generation of reactive oxygen species (ROS) and oxidative stress occurs in mitochondria as a consequence of an overload of glucose and oxidative phosphorylation. Endoplasmic reticulum (ER) stress plays an important role in oxidative stress, as it is also a source of ROS. The tight interconnection between both organelles through mitochondrial-associated membranes (MAMs) means that the ROS generated in mitochondria promote ER stress. Therefore, a state of stress and mitochondrial dysfunction are consequences of this vicious cycle. The implication of mitochondria in insulin release and the exposure of pancreatic β-cells to hyperglycemia make them especially susceptible to oxidative stress and mitochondrial dysfunction. In fact, crosstalk between both mechanisms is related with alterations in glucose homeostasis and can lead to the diabetes-associated insulin-resistance status. In the present review, we discuss the current knowledge of the relationship between oxidative stress, mitochondria, ER stress, inflammation, and lipotoxicity in T2D.

Mitochondria-associated ER membranes in glucose homeostasis and insulin resistance

2020 ◽  
Vol 319 (6) ◽  
pp. E1053-E1060
Author(s):  
Logan K. Townsend ◽  
Henver S. Brunetta ◽  
Marcelo A. S. Mori
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Endoplasmic Reticulum ◽  
Adipose Tissue ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Glucose Homeostasis ◽  
Calcium Homeostasis ◽  
Adenine Nucleotides ◽  
Current Controversy

Obesity and insulin resistance (IR) are associated with endoplasmic reticulum (ER) stress and mitochondrial dysfunction in several tissues. Although for many years mitochondrial and ER function were studied separately, these organelles also connect to produce interdependent functions. Communication occurs at mitochondria-associated ER membranes (MAMs) and regulates lipid and calcium homeostasis, apoptosis, and the exchange of adenine nucleotides, among other things. Recent evidence suggests that MAMs contribute to organelle, cellular, and systemic metabolism. In obesity and IR models, metabolic tissues such as the liver, skeletal muscle, pancreas, and adipose tissue present alterations in MAM structure or function. The purpose of this mini review is to highlight the MAM disruptions that occur in each tissue during obesity and IR and its relationship with glucose homeostasis and IR. We also discuss the current controversy that surrounds MAMs’ role in the development of IR.

scholarly journals Effects and mechanisms of caffeine to improve immunological and metabolic abnormalities in diet-induced obese rats

2018 ◽  
Vol 314 (5) ◽  
pp. E433-E447 ◽  
Author(s):  
Chih-Wei Liu ◽  
Hung-Cheng Tsai ◽  
Chia-Chang Huang ◽  
Chang-Youh Tsai ◽  
Yen-Bo Su ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Steatosis ◽  
Fatty Acid Synthase ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Ex Vivo ◽  
Intercellular Adhesion Molecule ◽  
Metabolic Abnormalities ◽  
Caffeine Treatment ◽  
Obese Rats

In obesity, there are no effective therapies for parallel immune and metabolic abnormalities, including systemic/tissue insulin-resistance/inflammation, adiposity and hepatic steatosis. Caffeine has anti-inflammation, antihepatic steatosis, and anti-insulin resistance effects. In this study, we evaluated the effects and molecular mechanisms of 6 wk of caffeine treatment (HFD-caf) on immunological and metabolic abnormalities of high-fat diet (HFD)-induced obese rats. Compared with HFD vehicle (HFD-V) rats, in HFD-caf rats the suppressed circulating immune cell inflammatory [TNFα, MCP-1, IL-6, intercellular adhesion molecule 1 (ICAM-1), and nitrite] profiles were accompanied by decreased liver, white adipose tissue (WAT), and muscle macrophages and their intracellular cytokine levels. Metabolically, the increase in metabolic rates reduced lipid accumulation in various tissues, resulting in reduced adiposity, lower fat mass, decreased body weight, amelioration of hepatic steatosis, and improved systemic/muscle insulin resistance. Further mechanistic approaches revealed an upregulation of tissue lipogenic [(SREBP1c, fatty acid synthase, acetyl-CoA carboxylase)/insulin-sensitizing (GLUT4 and p-IRS1)] markers in HFD-caf rats. Significantly, ex vivo experiments revealed that the cytokine release by the cocultured peripheral blood mononuclear cell (monocyte) and WAT (adipocyte), which are known to stimulate macrophage migration and hepatocyte lipogenesis, were lower in HFD-V groups than HFD-caf groups. Caffeine treatment simultaneously ameliorates immune and metabolic pathogenic signals present in tissue to normalize immunolgical and metabolic abnormalities found in HFD-induced obese rats.

scholarly journals Oleate Blocks Palmitate-Induced Abnormal Lipid Distribution, Endoplasmic Reticulum Expansion and Stress, and Insulin Resistance in Skeletal Muscle

Endocrinology ◽  
2011 ◽  
Vol 152 (6) ◽  
pp. 2206-2218 ◽  
Author(s):  
Gong Peng ◽  
Linghai Li ◽  
Yanbo Liu ◽  
Jing Pu ◽  
Shuyan Zhang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Insulin Sensitivity ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Dietary Fatty Acids ◽  
Akt Phosphorylation ◽  
Stress Relieving

Pathological elevation of plasma fatty acids reduces insulin sensitivity. Although several regulation pathways have been reported, the molecular mechanisms of insulin sensitivity remain elusive, especially in skeletal muscle where most glucose is consumed. This study focuses on how two major dietary fatty acids affect insulin signaling in skeletal muscle cells. Palmitic acid (PA) not only reduced insulin-stimulated phosphorylation of Akt but also induced endoplasmic reticulum (ER) expansion and ER stress. Relieving ER stress using 4-phenyl butyric acid blocked PA-mediated protein kinase R-like ER kinase phosphorylation and ER expansion and reversed the inhibitory effect of PA on insulin-stimulated Akt phosphorylation. Importantly, oleic acid (OA) could also recover PA-reduced Akt phosphorylation and abolish both PA-mediated ER expansion and ER stress. The competition between these two fatty acids was further verified in rat skeletal muscle using venous fatty acid infusion. 3H-labeled PA was converted mainly to active lipids (phospholipids and diacylglycerol) in the absence of OA, but to triacylglycerol in the presence of OA. Subcellular triacylglycerol and adipocyte differentiation-related protein from PA-treated cells cofractionated with the ER in the absence of OA but switched to the low-density fraction in the presence of OA. Taken together, these data suggest that the PA-mediated lipid composition and localization may cause ER expansion and consequently cause ER stress and insulin resistance in skeletal muscle.

scholarly journals Catestatin (Cst) protects the brain against ischemia/reperfusion injury through suppressing ER-stress and mitochondrial dysfunction

2020 ◽  
Author(s):  
Pei Bing ◽  
Chunjie Song ◽  
Zhengjiang Zhang ◽  
Shen Xin ◽  
Cui Qian
Keyword(s):  
Ischemic Stroke ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Reperfusion Injury ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Protective Function ◽  
The Brain

Abstract BackgroundCerebral stroke, known as a cerebral vascular accident (CVA), is one of the leading causes of long-term disability and the second leading cause of death worldwide. Despite amounts of advances that have been achieved in terms of the treatment of ischemic stroke. But thus far, clinically effective neuroprotectants remain elusive, which may mainly due to the lack of a complete understanding of molecular mechanisms of the stroke. Previous studies have been revealed that catestatin (Cst) is closely related to cardiovascular ischemia/reperfusion injuries. However, little is known about whether Cst is involved in the regulation of neuronal death processes during ischemia. MethodsIn the present study, we revealed a protective function of Cst on Rat neuron cell death in the setting of ischemia/reperfusion injury. ResultsWe found that Cst treatment significantly attenuated the deficits of hippocampal related behaviors. On mechanism, our data revealed that Cst administration remarkably reduced ER-stress and mitochondrial dysfunction caused by I/R injury, and subsequently protected brain cells from apoptosis. ConclusionIn sum, our results demonstrate that Cst ameliorates I/R injury-induced hippocampal-related behaviors deficits by protecting the neurons from I/R injury-induced ER-stress and mitochondrial dysfunction and apoptosis. Our findings may provide a promising novel neuroprotectant for ischemic stroke therapy.

scholarly journals Insulin-stimulated adiponectin secretion in pregnancy is mediated by inhibition of adiponectin ubiquitination and degradation and is impaired in obesity

2021 ◽  
Author(s):  
Irving L. M. H. Aye ◽  
Fredrick J. Rosario ◽  
Anita Kramer ◽  
Oddrun Kristiansen ◽  
Trond M. Michelsen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Gestational Diabetes ◽  
Er Stress ◽  
Pregnant Women ◽  
Fetal Growth ◽  
Molecular Mechanisms ◽  
Placental Function ◽  
Increased Risk ◽  
In Pregnancy

ABSTRACTIn pregnancy, adiponectin serves as an endocrine link between maternal adipose tissue, placental function and fetal growth, with low adiponectin promoting placental function and fetal growth. Circulating adiponectin levels are decreased in obese pregnant women and in gestational diabetes, which is believed to contribute to the insulin resistance and increased risk of fetal overgrowth associated with these conditions. However, the molecular mechanisms governing adiponectin secretion from maternal adipose tissues in pregnancy are poorly understood. Using visceral adipose tissue from lean and obese pregnant mice, we show that obesity in pregnancy is associated with adipose tissue inflammation, ER stress, insulin resistance, increased adiponectin ubiquitination and decreased total abundance of adiponectin. Moreover, adiponectin ubiquitination was increased in visceral fat of obese pregnant women as compared to lean pregnant women. We further observed that insulin prevents, whereas ER stress and inflammation promote, adiponectin ubiquitination and degradation in differentiated 3T3-L1 adipocytes. We have identified key molecular pathways regulating adiponectin secretion in pregnancy. This information will help us better understand the mechanisms controlling maternal insulin resistance and fetal growth in pregnancy and may provide a foundation for the development of strategies aimed at improving adiponectin production in pregnant women with obesity or gestational diabetes.

scholarly journals Exogenous acylated ghrelin promotes but un-acylated ghrelin prevents hepatic steatosis by modulating peripheral insulin resistance and hepatic oxidative and endoplasmic reticulum stress

2021 ◽  
Vol 7 (3) ◽  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Hepatic Steatosis ◽  
Fatty Acid Synthase ◽  
Lipid Synthesis ◽  
Acylated Ghrelin ◽  
Mrna Levels ◽  
Protein Levels

Objectives: This study tested the effects of acylated (AG and un-acylated ghrelin (UAG) on hepatic lipid synthesis and insulin resistance (IR) from prospective to their effect on endoplasmic reticulum stress and investigated the possible underlying mechanisms. Methods: Healthy rats were divided as 4 groups (n=12/each) as control, control + AG, control + UAG, and control + AG + UAG (1:1). GA or UAG were given subcutaneously (200 ng/kg/each) for 8 weeks. Results: AG increased fasting levels of glucose and insulin resistance, increased hepatic glucose production, and impaired glucose and insulin tolerance. Besides, it increased serum levels of free fatty acids (FFAs), enhanced serum and hepatic levels of triglycerides and cholesterol, and increased lipid deposition in the livers of rats. Concomitantly, it stimulated the mRNA levels of SREBP1/2, fatty acid synthase, and protein levels of all arms of ER stress including Xbp-1, CHOP, ATF-6, and p-eIF2α, thus activating lipid synthesis and ER stress. It also reduced protein levels of p-IRS (Tyr612), p-Akt (Ser307), and increased levels of ROS, TNF-α, IL-6, and protein levels of cleaved caspase-12, p-IRS (Ser307), and p-JNK (The183/Tyr186) in rats’ livers. Administration of UAG alone or in combination with AG produced contradictory effects. However, both AG and UAG significantly increased mRNA levels of AMPK and PPARα suggesting FAs oxidation. Conclusion: AG induces hepatic steatosis and suppresses hepatic insulin signaling mainly by inducing peripheral IR that is associated with hepatic oxidative stress, inflammation, and ER stress. However, UAG alone or in combination exerts opposite effects.

scholarly journals Deltamethrin Induces Apoptosis in Cerebrum Neurons of Quail via Promoting Endoplasmic Reticulum Stress and Mitochondrial Dysfunction

2021 ◽  
Author(s):  
Pengfei Wu ◽  
Bing Han ◽  
Qingyue Yang ◽  
Siyu Li ◽  
Xiaoqiao Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Chronic Exposure ◽  
Molecular Mechanisms ◽  
Atp Content ◽  
Histological Changes ◽  
Real Time Quantitative Pcr ◽  
Induced Apoptosis

Abstract Deltamethrin (DLM) is a widely used and highly effective insecticide. DLM exposure is harmful to animal and human. Quail, as a bird model, has been widely used in the toxicology field. However, there is little information available in the literature about quail cerebrum damage caused by DLM. Here, we investigated the effect of DLM on quail cerebrum neurons. Four groups of healthy quails were assigned (10 quails in each group), respectively given 0, 15, 30, and 45 mg/kg DLM by gavage for 12 weeks. Through the measurements of quail cerebrum, it was found that DLM exposure induced obvious histological changes, oxidative stress, and neurons apoptosis. To further explore the possible molecular mechanisms, we performed real-time quantitative PCR to detect the expression of endoplasmic reticulum (ER) stress-related mRNA. In addition, we detected ATP content in quail cerebrum to evaluate the functional status of mitochondria. The study showed that DLM exposure significantly increased the expression of ER stress-related mRNA and decreased ATP content in quail cerebrum. These results suggest that chronic exposure to DLM induces apoptosis of quail cerebrum neurons via promoting ER stress and mitochondrial dysfunction. Furthermore, our results provide a novel explanation for DLM-induced apoptosis of avian cerebrum neurons.

scholarly journals Hepatic Krüppel-like factor 16 (KLF16) targets PPARα to improve steatohepatitis and insulin resistance

Gut ◽  
2020 ◽  
pp. gutjnl-2020-321774
Author(s):  
Nannan Sun ◽  
Chuangpeng Shen ◽  
Lei Zhang ◽  
Xiaojie Wu ◽  
Yuanyuan Yu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Redox Balance ◽  
Luciferase Reporter ◽  
Lipid Deposition ◽  
Mitochondrial Stress ◽  
Hepatic Lipid ◽  
Gene Assay

ObjectiveImpaired hepatic fatty acids oxidation results in lipid accumulation and redox imbalance, promoting the development of fatty liver diseases and insulin resistance. However, the underlying pathogenic mechanism is poorly understood. Krüppel-like factor 16 (KLF16) is a transcription factor that abounds in liver. We explored whether and by what mechanisms KLF16 affects hepatic lipid catabolism to improve hepatosteatosis and insulin resistance.DesignKLF16 expression was determined in patients with non-alcoholic fatty liver disease (NAFLD) and mice models. The role of KLF16 in the regulation of lipid metabolism was investigated using hepatocyte-specific KLF16-deficient mice fed a high-fat diet (HFD) or using an adenovirus/adeno-associated virus to alter KLF16 expression in mouse primary hepatocytes (MPHs) and in vivo livers. RNA-seq, luciferase reporter gene assay and ChIP analysis served to explore the molecular mechanisms involved.ResultsKLF16 expression was decreased in patients with NAFLD, mice models and oleic acid and palmitic acid (OA and PA) cochallenged hepatocytes. Hepatic KLF16 knockout impaired fatty acid oxidation, aggravated mitochondrial stress, ROS burden, advancing hepatic steatosis and insulin resistance. Conversely, KLF16 overexpression reduced lipid deposition and improved insulin resistance via directly binding the promoter of peroxisome proliferator-activated receptor α (PPARα) to accelerate fatty acids oxidation and attenuate mitochondrial stress, oxidative stress in db/db and HFD mice. PPARα deficiency diminished the KLF16-evoked protective effects against lipid deposition in MPHs. Hepatic-specific PPARα overexpression effectively rescued KLF16 deficiency-induced hepatic steatosis, altered redox balance and insulin resistance.ConclusionsThese findings prove that a direct KLF16–PPARα pathway closely links hepatic lipid homeostasis and redox balance, whose dysfunction promotes insulin resistance and hepatic steatosis.

Sign in / Sign up

Export Citation Format

Share Document