Macrophage cholesterol homeostasis and metabolic diseases: critical role of cholesteryl ester mobilization

Although numerous functions of inositol-requiring enzyme 1α (IRE1α) have been identified, a role of IRE1α in pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus is largely unknown. Here, we showed that mice lacking IRE1α specifically in POMC neurons (PIKO) are lean and resistant to high-fat diet-induced obesity and obesity-related insulin resistance, liver steatosis and leptin resistance. Furthermore, PIKO mice had higher energy expenditure, probably due to increased thermogenesis in brown adipose tissue. Additionally, α-melanocyte-stimulating hormone production was increased in the hypothalamus of PIKO mice. These results demonstrate that IRE1α in POMC neurons plays a critical role in the regulation of obesity and obesity-related metabolic disorders. Our results also suggest that IRE1α is not only an endoplasmic reticulum stress sensor, but also a new potential therapeutic target for obesity and obesity-related metabolic diseases.

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Defective liver glycogen autophagy related to hyperinsulinemia in intrauterine growth-restricted newborn wistar rats

Scientific Reports ◽

10.1038/s41598-020-74702-9 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Juan de Toro-Martín ◽

Tamara Fernández-Marcelo ◽

Águeda González-Rodríguez ◽

Fernando Escrivá ◽

Ángela M. Valverde ◽

...

Keyword(s):

Wistar Rats ◽

Metabolic Diseases ◽

Critical Role ◽

Liver Glycogen ◽

Hormonal Control ◽

Standard Diet ◽

Major Organ ◽

Mtorc1 Pathway

Abstract Maternal malnutrition plays a critical role in the developmental programming of later metabolic diseases susceptibility in the offspring, such as obesity and type 2 diabetes. Because the liver is the major organ that produces and supplies blood glucose, we aimed at defining the potential role of liver glycogen autophagy in the programming of glucose metabolism disturbances. To this end, newborns were obtained from pregnant Wistar rats fed ad libitum with a standard diet or 65% food-restricted during the last week of gestation. We found that newborns from undernourished mothers showed markedly high basal insulin levels whereas those of glucagon were decreased. This unbalance led to activation of the mTORC1 pathway and inhibition of hepatic autophagy compromising the adequate handling of glycogen in the very early hours of extrauterine life. Restoration of autophagy with rapamycin but not with glucagon, indicated no defect in autophagy machinery per se, but in signals triggered by glucagon. Taken together, these results support the notion that hyperinsulinemia is an important mechanism by which mobilization of liver glycogen by autophagy is defective in food-restricted animals. This early alteration in the hormonal control of liver glycogen autophagy may influence the risk of developing metabolic diseases later in life.

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Long Non-Coding RNA Associated with Cholesterol Homeostasis and Its Involvement in Metabolic Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21218337 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8337

Author(s):

Kang-Hoon Lee ◽

Hyeon-Ji Hwang ◽

Je-Yoel Cho

Keyword(s):

Metabolic Diseases ◽

Disease Process ◽

Cholesterol Homeostasis ◽

Cell Component ◽

Non Coding Rna ◽

Systemic Level ◽

Development Processes ◽

Non Coding Rnas ◽

Long Non Coding Rna

Cholesterol is an essential cell component that functions to create and maintain all kinds of cell membranes and lipoprotein particles. It is crucial to maintain the proper amount of cholesterol at both the cellular and systemic level. Recently, the importance of cholesterol has been reported not only in various cell development processes but also in the development of diseases. Furthermore, the involvement of long non-coding RNAs (lncRNAs), which are regarded as important epigenetic regulators in gene expression, has also been reported in cholesterol homeostasis. It is thus necessary to summarize the research on lncRNAs related to cholesterol with increased interest. This review organized the role of lncRNAs according to the major issues in cholesterol homeostasis: efflux, metabolism and synthesis, and disease process.

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Age and Dietary Vitamin C Intake Affect Brain Physiology in Genetically Modified Mice Expressing Human Lipoprotein(A) and Unable to Synthesize Vitamin C

Current Aging Science ◽

10.2174/1874609814666210706170326 ◽

2021 ◽

Vol 14 ◽

Author(s):

Lei Shi ◽

Aleksandra Niedzwiecki ◽

Matthias Rath

Keyword(s):

Vitamin C ◽

Oxidative Damage ◽

Critical Role ◽

Cholesterol Homeostasis ◽

Dietary Vitamin ◽

Brain Health ◽

Lipoprotein A ◽

Vitamin C Deficiency ◽

The Brain

Aims: Lipoprotein (a) deposition in coronary vascular plaques and cerebral vessels is a recognized risk factor for cardiovascular disease, and research supports its role as a “repair factor” in vascular walls weakened by vitamin C deficiency. Background: Humans depend on dietary vitamin C as an important antioxidant, and as a cofactor in collagen synthesis, yet are prone to vitamin C deficiency. The brain is the one with the highest vitamin C content, due to its high oxygen consumption and oxidative stress. It has been shown that brain aging is accompanied by accumulated oxidative damage, which can lead to memory decline and neurological diseases. Objective: Our transgenic mouse, Gulo (-/-); Lp(a)+, presents a unique model for the study of key aspects of human metabolism with respect to a lack of internal vitamin C synthesis and the production of human Lipoprotein(a). Method: This mouse model was used in our study to investigate the effects of prolonged intake of low and high levels of vitamin C, at different ages, on oxidative damage, cholesterol levels and Lipoprotein(a) deposition in the brain. Result: The results show that a long-term high vitamin C intake is important in maintaining brain cholesterol homeostasis and preventing oxidative damage in Gulo(-/-);Lp(a)+ mice as they age. Moreover, we observed that the formation of brain Lipoprotein(a) deposits was negatively correlated with brain level of vitamin C, thereby confirming its role as a stability factor for an impaired extracellular matrix. Conclusion: Our study emphasizes the critical role of vitamin C in protecting brain health as we age. Other: Our findings show that optimal vitamin C intake from early life to old age is important in brain health to prevent oxidative stress damage and to maintain cholesterol homeostasis in the brain. More importantly, negative correlation between brain ascorbic levels and the formation of Lp(a) deposit on the choroid plexus further emphasizes the critical role of vitamin C in protecting brain health throughout the normal aging process.

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Oxysterol Nuclear Receptor LXRβ Regulates Cholesterol Homeostasis and Contractile Function in Mouse Uterus

Journal of Biological Chemistry ◽

10.1074/jbc.m606718200 ◽

2006 ◽

Vol 282 (7) ◽

pp. 4693-4701 ◽

Cited By ~ 35

Author(s):

Kevin Mouzat ◽

Magali Prod'Homme ◽

David H. Volle ◽

Benoit Sion ◽

Pierre Déchelotte ◽

...

Keyword(s):

Cholesteryl Ester ◽

Nuclear Receptor ◽

Target Genes ◽

Contractile Function ◽

Contractile Activity ◽

Critical Role ◽

Cholesterol Homeostasis ◽

Protective Mechanism ◽

Mouse Uterus ◽

Expression Of Genes

The uterus is an organ where lipid distribution plays a critical role for its function. Here we show that nuclear receptor for oxysterols LXRβ prevents accumulation of cholesteryl esters in mouse myometrium by controlling expression of genes involved in cholesterol efflux and storage (abca1 and abcg1). Upon treatment with an LXR agonist that mimics activation by oxysterols, expression of these target genes was increased in wild-type mice, whereas under basal conditions, lxrα;β-/- mice exhibited a marked decrease in abcg1 accumulation. This change resulted in a phenotype of cholesteryl ester accumulation. Besides, a defect of contractile activity induced by oxytocin or PGF2α was observed in mice lacking LXRβ. These results imply that LXRβ provides a safety valve to limit cholesteryl ester levels as a basal protective mechanism in the uterus against cholesterol accumulation and is necessary for a correct induction of contractions.

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MicroRNA Regulation of Cholesterol Metabolism

Cholesterol ◽

10.1155/2012/847849 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 40

Author(s):

Noemi Rotllan ◽

Carlos Fernández-Hernando

Keyword(s):

Type Ii Diabetes ◽

Cholesterol Metabolism ◽

Critical Role ◽

Cholesterol Homeostasis ◽

Microrna Regulation ◽

Fine Regulation ◽

Lipid Metabolism Genes ◽

Pathologic Processes ◽

Metabolic Adjustment

Disruption of cellular cholesterol balance results in pathologic processes including atherosclerosis, metabolic syndrome, type II diabetes and Alzheimer’s disease. Maintenance of cholesterol homeostasis requires constant metabolic adjustment, achieved partly through the fine regulation of the classical transcription factors (e.g., by SREBP and LXR), but also through members of a class of noncoding RNAs termed miRNAs. Some miRNAs have now been identified to be potent post-transcriptional regulators of lipid metabolism genes, including miR-122, miR-33, miR-758, and miR-106b. Different strategies have been developed to modulate miRNA effects for therapeutic purposes. The promise demonstrated by the use of anti-miRs in human preclinical studies, in the case of miR-122, raises the possibility that miR-33, miR-758, and miR-106b may become viable therapeutic targets in future. This review summarizes the evidence for a critical role of some miRNAs in regulating cholesterol metabolism and suggests novel ways to manage dyslipidemias and cardiovascular diseases.

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Endothelial TFEB (Transcription Factor EB) Improves Glucose Tolerance via Upregulation of IRS (Insulin Receptor Substrate) 1 and IRS2

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.315310 ◽

2020 ◽

Author(s):

Jinjian Sun ◽

Haocheng Lu ◽

Wenying Liang ◽

Guizhen Zhao ◽

Lu Ren ◽

...

Keyword(s):

Glucose Tolerance ◽

Transgenic Mice ◽

High Fat Diet ◽

Metabolic Diseases ◽

Critical Role ◽

Insulin Receptor Substrate ◽

High Fat ◽

Transcription Factor Eb

Objective: Vascular endothelial cells (ECs) play a critical role in maintaining vascular homeostasis. Aberrant EC metabolism leads to vascular dysfunction and metabolic diseases. TFEB (transcription factor EB), a master regulator of lysosome biogenesis and autophagy, has protective effects on vascular inflammation and atherosclerosis. However, the role of endothelial TFEB in metabolism remains to be explored. In this study, we sought to investigate the role of endothelial TFEB in glucose metabolism and underlying molecular mechanisms. Approach and Results: To determine whether endothelial TFEB is critical for glucose metabolism in vivo, we utilized EC-selective TFEB knockout and EC-selective TFEB transgenic mice fed a high-fat diet. EC-selective TFEB knockout mice exhibited significantly impaired glucose tolerance compared with control mice. Consistently, EC-selective TFEB transgenic mice showed improved glucose tolerance. In primary human ECs, small interfering RNA-mediated TFEB knockdown blunts Akt (AKT serine/threonine kinase) signaling. Adenovirus-mediated overexpression of TFEB consistently activates Akt and significantly increases glucose uptake in ECs. Mechanistically, TFEB upregulates IRS1 and IRS2 (insulin receptor substrate 1 and 2). TFEB increases IRS2 transcription measured by reporter gene and chromatin immunoprecipitation assays. Furthermore, we found that TFEB increases IRS1 protein via downregulation of microRNAs (miR-335, miR-495, and miR-548o). In vivo, Akt signaling in the skeletal muscle and adipose tissue was significantly impaired in EC-selective TFEB knockout mice and consistently improved in EC-selective TFEB transgenic mice on high-fat diet. Conclusions: Our data revealed a critical role of TFEB in endothelial metabolism and suggest that TFEB constitutes a potential molecular target for the treatment of vascular and metabolic diseases.

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Critical role of neutral cholesteryl ester hydrolase 1 in cholesteryl ester hydrolysis in murine macrophages

The Journal of Lipid Research ◽

10.1194/jlr.m047787 ◽

2014 ◽

Vol 55 (10) ◽

pp. 2033-2040 ◽

Cited By ~ 17

Author(s):

Kent Sakai ◽

Masaki Igarashi ◽

Daisuke Yamamuro ◽

Taichi Ohshiro ◽

Shuichi Nagashima ◽

...

Keyword(s):

Cholesteryl Ester ◽

Critical Role ◽

Ester Hydrolysis ◽

Cholesteryl Ester Hydrolase ◽

Murine Macrophages ◽

Ester Hydrolase

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Adiponectin as a Potential Biomarker for Pregnancy Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms22031326 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1326

Author(s):

Carmen Pheiffer ◽

Stephanie Dias ◽

Babalwa Jack ◽

Nompumelelo Malaza ◽

Sumaiya Adam

Keyword(s):

Pregnancy Complications ◽

Energy Homeostasis ◽

Metabolic Diseases ◽

Early Recognition ◽

Critical Role ◽

Future Research ◽

Potential Biomarker ◽

Mother And Child

Adiponectin is an adipocyte-derived hormone that plays a critical role in energy homeostasis, mainly attributed to its insulin-sensitizing properties. Accumulating studies have reported that adiponectin concentrations are decreased during metabolic diseases, such as obesity and type 2 diabetes, with an emerging body of evidence providing support for its use as a biomarker for pregnancy complications. The identification of maternal factors that could predict the outcome of compromised pregnancies could act as valuable tools that allow the early recognition of high-risk pregnancies, facilitating close follow-up and prevention of pregnancy complications in mother and child. In this review we consider the role of adiponectin as a potential biomarker of disorders associated with pregnancy. We discuss common disorders associated with pregnancy (gestational diabetes mellitus, preeclampsia, preterm birth and abnormal intrauterine growth) and highlight studies that have investigated the potential of adiponectin to serve as biomarkers for these disorders. We conclude the review by recommending strategies to consider for future research.

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