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MIGA2 Links Mitochondria, the ER, and Lipid Droplets and Promotes De Novo Lipogenesis in Adipocytes.Molecular Cell Dec 2019Physical contact between organelles is vital to the function of eukaryotic cells. Lipid droplets (LDs) are dynamic organelles specialized in lipid storage that interact...
Physical contact between organelles is vital to the function of eukaryotic cells. Lipid droplets (LDs) are dynamic organelles specialized in lipid storage that interact physically with mitochondria in several cell types. The mechanisms coupling these organelles are, however, poorly understood, and the cell-biological function of their interaction remains largely unknown. Here, we discover in adipocytes that the outer mitochondrial membrane protein MIGA2 links mitochondria to LDs. We identify an amphipathic LD-targeting motif and reveal that MIGA2 binds to the membrane proteins VAP-A or VAP-B in the endoplasmic reticulum (ER). We find that in adipocytes MIGA2 is involved in promoting triglyceride (TAG) synthesis from non-lipid precursors. Our data indicate that MIGA2 links reactions of de novo lipogenesis in mitochondria to TAG production in the ER, thereby facilitating efficient lipid storage in LDs. Based on its presence in many tissues, MIGA2 is likely critical for lipid and energy homeostasis in a wide spectrum of cell types.
Topics: 3T3 Cells; Adipocytes; Animals; COS Cells; Cell Differentiation; Chlorocebus aethiops; Endoplasmic Reticulum; HEK293 Cells; Humans; Lipid Droplets; Lipogenesis; Membrane Proteins; Mice; Mitochondria; Mitochondrial Proteins; Triglycerides; Vesicular Transport Proteins
PubMed: 31628041
DOI: 10.1016/j.molcel.2019.09.011 -
Nutrients Sep 2019Recent evidences have linked indole-3-acetic acid (IAA), a gut microbiota-derived metabolite from dietary tryptophan, with the resistance to liver diseases. However,...
Recent evidences have linked indole-3-acetic acid (IAA), a gut microbiota-derived metabolite from dietary tryptophan, with the resistance to liver diseases. However, data supporting IAA-mediated protection against nonalcoholic fatty liver disease (NAFLD) from an in vivo study is lacking. In this study, we assessed the role of IAA in attenuating high-fat diet (HFD)-induced NAFLD in male C57BL/6 mice. Administration of IAA (50 mg/kg body weight) by intraperitoneal injection was found to alleviate HFD-induced elevation in fasting blood glucose and homeostasis model assessment of insulin resistance (HOMA-IR) index as well as plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), and glutamic-pyruvic transaminase (GPT) activity. Histological examination further presented the protective effect of IAA on liver damage induced by HFD feeding. HFD-induced an increase in liver total triglycerides and cholesterol, together with the upregulation of genes related to lipogenesis including sterol regulatory element binding-protein 1 (Srebf1), steraroyl coenzyme decarboxylase 1 (Scd1), peroxisome proliferator-activated receptor gamma (PPARγ), acetyl-CoA carboxylase 1 (Acaca), and glycerol-3-phosphate acyltransferase, mitochondrial (Gpam), which were mitigated by IAA treatment. The results of reactive oxygen species (ROS) and malonaldehyde (MDA) level along with superoxide dismutase (SOD) activity and glutathione (GSH) content in liver tissue evidenced the protection of IAA against HFD-induced oxidative stress. Additionally, IAA attenuated the inflammatory response of liver in mice exposed to HFD as shown by the reduction in the F4/80-positive macrophage infiltration and the expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α). In conclusion, our findings uncover that IAA alleviates HFD-induced hepatotoxicity in mice, which proves to be associated with the amelioration in insulin resistance, lipid metabolism, and oxidative and inflammatory stress.
Topics: Animals; Indoleacetic Acids; Inflammation; Lipids; Lipogenesis; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Oxidative Stress
PubMed: 31484323
DOI: 10.3390/nu11092062 -
Cell Metabolism Nov 2023The PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the...
The PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the effect of this variant on hepatic metabolism in homozygous carriers and non-carriers under multiple physiological conditions with state-of-the-art stable isotope techniques. After an overnight fast, carriers had higher plasma β-hydroxybutyrate concentrations and lower hepatic de novo lipogenesis (DNL) compared to non-carriers. After a mixed meal, fatty acids were channeled toward ketogenesis in carriers, which was associated with an increase in hepatic mitochondrial redox state. During a ketogenic diet, carriers manifested increased rates of intrahepatic lipolysis, increased plasma β-hydroxybutyrate concentrations, and decreased rates of hepatic mitochondrial citrate synthase flux. These studies demonstrate that homozygous PNPLA3 I148M carriers have hepatic mitochondrial dysfunction leading to reduced DNL and channeling of carbons to ketogenesis. These findings have implications for understanding why the PNPLA3 variant predisposes to progressive liver disease.
Topics: Humans; Lipogenesis; 3-Hydroxybutyric Acid; Liver; Non-alcoholic Fatty Liver Disease; Mitochondria; Genetic Predisposition to Disease
PubMed: 37909034
DOI: 10.1016/j.cmet.2023.10.008 -
Developmental Cell Mar 2022Tissues and cells require fuel and cellular building blocks to respond to proliferative cues. In this issue of Developmental Cell, Vaidyanathan and colleagues modulate...
Tissues and cells require fuel and cellular building blocks to respond to proliferative cues. In this issue of Developmental Cell, Vaidyanathan and colleagues modulate yes-associated protein (YAP) signaling and its downstream targets, together with phenotyping and metabolic tracing, to determine the central role of YAP in lipogenesis and associated liver growth.
Topics: Cell Proliferation; Lipogenesis; Mechanistic Target of Rapamycin Complex 1; Sterol Regulatory Element Binding Protein 1; YAP-Signaling Proteins
PubMed: 35349794
DOI: 10.1016/j.devcel.2022.03.003 -
Nutrients Aug 2020Macroalgae have attracted great interest for their potential applications in nutraceutical and pharmaceutical industries as source of bioactive medicinal products and... (Review)
Review
Macroalgae have attracted great interest for their potential applications in nutraceutical and pharmaceutical industries as source of bioactive medicinal products and food ingredients. This review gathers data from and studies addressing the anti-obesity effects of macroalgae. Great consensus exists in all reported studies concerning the reduction induced by seaweed extracts in the expression of transcriptional factors controlling adipogenesis. In animals, macroalgae reduced body fat accumulation and prevented other obesity features, such as dyslipidemia, insulin resistance and fatty liver. These effects are not due to food intake reduction, since few studies have reported such event. Indeed, the effects on metabolic pathways in target tissues/organs seem to play a more relevant role. Macroalgae can reduce de novo lipogenesis, limiting fatty acid availability for triglyceride synthesis in white adipose tissue. This effect has been observed in both cell cultures and adipose tissue from animals treated with macroalgae extracts. In addition, increased fatty acid oxidation and thermogenic capacity, as well as a shift towards healthier gut microbiota composition may contribute to the body fat-lowering effect of macroalgae. Studies in humans are needed to determine whether macroalgae can represent a feasible tool to prevent and/or manage overweight and obesity.
Topics: Adipogenesis; Adipose Tissue, White; Animals; Anti-Obesity Agents; Fatty Acids; Lipogenesis; Liver; Obesity; Oxidation-Reduction; Plant Extracts; Seaweed; Thermogenesis
PubMed: 32784488
DOI: 10.3390/nu12082378 -
JCI Insight Mar 2023Cancer stem-like cells (CSCs) are critically involved in cancer metastasis and chemoresistance, acting as one major obstacle in clinical practice. While accumulating...
Cancer stem-like cells (CSCs) are critically involved in cancer metastasis and chemoresistance, acting as one major obstacle in clinical practice. While accumulating studies have implicated the metabolic reprogramming of CSCs, mitochondrial dynamics in such cells remain poorly understood. Here we pinpointed OPA1hi with mitochondrial fusion as a metabolic feature of human lung CSCs, licensing their stem-like properties. Specifically, human lung CSCs exerted enhanced lipogenesis, inducing OPA1 expression via transcription factor SAM Pointed Domain containing ETS transcription Factor (SPDEF). In consequence, OPA1hi promoted mitochondrial fusion and stemness of CSCs. Such lipogenesishi, SPDEFhi, and OPA1hi metabolic adaptions were verified with primary CSCs from lung cancer patients. Accordingly, blocking lipogenesis and mitochondrial fusion efficiently impeded CSC expansion and growth of organoids derived from patients with lung cancer. Together, lipogenesis regulates mitochondrial dynamics via OPA1 for controlling CSCs in human lung cancer.
Topics: Humans; Mitochondrial Dynamics; Lipogenesis; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Transcription Factors
PubMed: 36809297
DOI: 10.1172/jci.insight.158429 -
Diabetes Apr 2020Hepatosteatosis, which is frequently associated with development of metabolic syndrome and insulin resistance, manifests when triglyceride (TG) input in the liver is... (Review)
Review
Hepatosteatosis, which is frequently associated with development of metabolic syndrome and insulin resistance, manifests when triglyceride (TG) input in the liver is greater than TG output, resulting in the excess accumulation of TG. Dysregulation of lipogenesis therefore has the potential to increase lipid accumulation in the liver, leading to insulin resistance and type 2 diabetes. Recently, efforts have been made to examine the epigenetic regulation of metabolism by histone-modifying enzymes that alter chromatin accessibility for activation or repression of transcription. For regulation of lipogenic gene transcription, various known lipogenic transcription factors, such as USF1, ChREBP, and LXR, interact with and recruit specific histone modifiers, directing specificity toward lipogenesis. Alteration or impairment of the functions of these histone modifiers can lead to dysregulation of lipogenesis and thus hepatosteatosis leading to insulin resistance and type 2 diabetes.
Topics: Animals; Diabetes Mellitus; Epigenesis, Genetic; Fatty Liver; Humans; Insulin Resistance; Lipogenesis; Liver; Metabolic Syndrome
PubMed: 32198196
DOI: 10.2337/dbi18-0032 -
Genes Mar 2021In the poultry industry, excessive fat deposition is considered an undesirable factor, affecting feed efficiency, meat production cost, meat quality, and consumer's... (Review)
Review
In the poultry industry, excessive fat deposition is considered an undesirable factor, affecting feed efficiency, meat production cost, meat quality, and consumer's health. Efforts to reduce fat deposition in economically important animals, such as chicken, can be made through different strategies; including genetic selection, feeding strategies, housing, and environmental strategies, as well as hormone supplementation. Recent investigations at the molecular level have revealed the significant role of the transcriptional and post-transcriptional regulatory networks and their interaction on modulating fat metabolism in chickens. At the transcriptional level, different transcription factors are known to regulate the expression of lipogenic and adipogenic genes through various signaling pathways, affecting chicken fat metabolism. Alternatively, at the post-transcriptional level, the regulatory mechanism of microRNAs (miRNAs) on lipid metabolism and deposition has added a promising dimension to understand the structural and functional regulatory mechanism of lipid metabolism in chicken. Therefore, this review focuses on the progress made in unraveling the molecular function of genes, transcription factors, and more notably significant miRNAs responsible for regulating adipogenesis, lipogenesis, and fat deposition in chicken. Moreover, a better understanding of the molecular regulation of lipid metabolism will give researchers novel insights to use functional molecular markers, such as miRNAs, for selection against excessive fat deposition to improve chicken production efficiency and meat quality.
Topics: Abdominal Fat; Adipogenesis; Animals; Chickens; Gene Expression Regulation; Gene Regulatory Networks; Humans; Lipid Metabolism; Lipogenesis
PubMed: 33805667
DOI: 10.3390/genes12030414 -
Diabetes Jul 2016Recent studies have shown that in addition to their traditionally recognized functions as building blocks, energy stores, or hazardous intermediates, lipids also have... (Review)
Review
Recent studies have shown that in addition to their traditionally recognized functions as building blocks, energy stores, or hazardous intermediates, lipids also have the ability to act as signaling molecules with potent effects on systemic metabolism and metabolic diseases. This Perspective highlights this somewhat less apparent biology of lipids, especially focusing on de novo lipogenesis as a process that gives rise to key messenger molecules mediating interorgan communication. Elucidating the mechanisms of lipid-dependent coordination of metabolism promises invaluable insights into the understanding of metabolic diseases and may contribute to the development of a new generation of preventative and therapeutic approaches.
Topics: Adipose Tissue; Animals; Fatty Acids; Lipogenesis; Liver; Signal Transduction
PubMed: 27288005
DOI: 10.2337/db16-0251 -
The Journal of Clinical Investigation Dec 2023Worldwide, over 800 million people are affected by kidney disease, yet its pathogenesis remains elusive, hindering the development of novel therapeutics. In this study,...
Worldwide, over 800 million people are affected by kidney disease, yet its pathogenesis remains elusive, hindering the development of novel therapeutics. In this study, we used kidney-specific expression of quantitative traits and single-nucleus open chromatin analysis to show that genetic variants linked to kidney dysfunction on chromosome 20 target the acyl-CoA synthetase short-chain family 2 (ACSS2). By generating ACSS2-KO mice, we demonstrated their protection from kidney fibrosis in multiple disease models. Our analysis of primary tubular cells revealed that ACSS2 regulated de novo lipogenesis (DNL), causing NADPH depletion and increasing ROS levels, ultimately leading to NLRP3-dependent pyroptosis. Additionally, we discovered that pharmacological inhibition or genetic ablation of fatty acid synthase safeguarded kidney cells against profibrotic gene expression and prevented kidney disease in mice. Lipid accumulation and the expression of genes related to DNL were elevated in the kidneys of patients with fibrosis. Our findings pinpoint ACSS2 as a critical kidney disease gene and reveal the role of DNL in kidney disease.
Topics: Animals; Humans; Mice; Acetate-CoA Ligase; Fibrosis; Kidney; Kidney Diseases; Kidney Tubules; Lipogenesis
PubMed: 38051585
DOI: 10.1172/JCI172963