Biology subjects

Hotamisligil, G. S.

Publications and source records attributed to Hotamisligil, G. S..

10 recordsLinked to original sources

bioRxiv2025

Cholesterol-Responsive Interaction of NFE2L1-INSIG1 Controls VLDL Secretion and MASH Pathogenesis

Cholesterol overload drives metabolic dysfunction-associated steatohepatitis (MASH). While the liver maintains homeostasis by exporting cholesterol via very low-density lipoprotein (VLDL) secretion, this process is paradoxically suppressed under cholesterol excess by insulin-induced gene 1 (INSIG1), which inhibits sterol regulatory element-binding protein 1 (SREBP1) activity. How VLDL secretion persists during cholesterol overload to prevent lipotoxicity remains unresolved. We identify a cholesterol-responsive interaction between nuclear factor erythroid 2 related factor-1 (NFE2L1) and INSIG1 that sustains cholesterol balance. Hepatic NFE2L1 deficiency elevates INSIG1 levels, suppressing SREBP1 activation and impairing VLDL secretion, leading to cholesterol accumulation and liver injury. Mechanistically, NFE2L1 binds to INSIG1 via its N-terminal homology box 2 (NHB2) domain, with cholesterol enhancing this interaction to drive INSIG1 degradation and SREBP1 activation. In NFE2L1-deficient mice, wild-type NFE2L1 restores SREBP1 activity and VLDL secretion, while the NHB2-deleted mutant ({Delta}NHB2) fails. Lipidomics reveal that NFE2L1 deficiency reduces serum triglyceride composition, restored exclusively by wild-type NFE2L1. In a murine MASH model, NFE2L1 overexpression activates SREBP1/2, enhances cholesterol secretion, and alleviates liver injury, inflammation and fibrosis, without elevating atherogenic lipoproteins due to compensatory LDL receptor upregulation. Our findings resolve the paradox of cholesterol-driven VLDL secretion and establish the NFE2L1-INSIG1 axis as a therapeutic target for metabolic diseases.

physiology↗

bioRxiv2024

An Adipo-Pulmonary Axis Mediated by FABP4 Hormone Defines a Therapeutic Target Against Obesity-Induced Airway Disease

Obesity-related airway disease is a clinical condition without a clear description and effective treatment. Here, we define this pathology and its unique properties, which differ from classic asthma phenotypes, and identify a novel adipo-pulmonary axis mediated by FABP4 hormone as a critical mediator of obesity-induced airway disease. Through detailed analysis of murine models and human samples, we elucidate the dysregulated lipid metabolism and immunometabolic responses within obese lungs, particularly highlighting the stress response activation and downregulation of surfactant-related genes, notably SftpC. We demonstrate that FABP4 deficiency mitigates these alterations, demonstrating a key role in obesity-induced airway disease pathogenesis. Importantly, we identify adipose tissue as the source of FABP4 hormone in the bronchoalveolar space and describe strong regulation in the context of human obesity, particularly among women. Finally, our exploration of antibody-mediated targeting of circulating FABP4 unveils a novel therapeutic avenue, addressing a pressing unmet need in managing obesity-related airway disease. These findings not only define the presence of a critical adipo-pulmonary endocrine link but also present FABP4 as a therapeutic target for managing this unique airway disease that we refer to as fatty lung disease associated with obesity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=162 HEIGHT=200 SRC="FIGDIR/small/603433v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@c1449corg.highwire.dtl.DTLVardef@7f6869org.highwire.dtl.DTLVardef@9fd41corg.highwire.dtl.DTLVardef@11eb408_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryInvestigating FABP4s pivotal role in obesity-driven airway disease, this study unveils an adipo-pulmonary axis with potential therapeutic implications.

physiology↗

bioRxiv2024

FABP4 as a Therapeutic Host Target Controlling SARS-CoV2 Infection

Host metabolic fitness is a critical determinant of infectious disease outcomes. Obesity, aging, and other related metabolic disorders are recognized as high-risk disease modifiers for respiratory infections, including coronavirus infections, though the underlying mechanisms remain unknown. Our study highlights fatty acid-binding protein 4 (FABP4), a key regulator of metabolic dysfunction and inflammation, as a modulator of SARS-CoV-2 pathogenesis, correlating strongly with disease severity in COVID-19 patients. We demonstrate that loss of FABP4 function, by genetic or pharmacological means, reduces SARS-CoV2 replication and disrupts the formation of viral replication organelles in adipocytes and airway epithelial cells. Importantly, FABP4 inhibitor treatment of infected hamsters diminished lung viral titers, alleviated lung damage and reduced collagen deposition. These findings highlight the therapeutic potential of targeting host metabolism in limiting coronavirus replication and mitigating the pathogenesis of infection.

microbiology↗

bioRxiv2023

Hepatic IRE1 Protects Against Septic Cardiac Failure

SUMMARYMetabolic reprogramming in response to infection plays a critical role for septic survival. During a septic episode, the heart heavily relies on hepatic lipid particles to prevent heart damage and failure. Inositol- Requiring Enzyme 1 (IRE1) is the most conserved unfolded protein response (UPR) regulator that governs homeostasis of the endoplasmic reticulum (ER), the major site for lipid synthesis and processing. Here we show that hepatocyte IRE1 is indispensable for protecting against septic mortality in two different rodent models of experimental sepsis. The protective effect of hepatic IRE1 was not attributed to the inflammatory response since hepatic IRE1 deletion did not alter hepatic or systemic cytokine response. However, loss of IRE1 in the liver significantly augmented septic cardiac dysfunction in part due to a skewed immune-metabolic balance. Lipidomic and metabolomic analyses further revealed that loss of IRE1 in the liver compromised adaptive intrahepatic and circulating lipid reprogramming, including VLDL, in response to septic challenge. Furthermore, we identified that the protective effects against septic mortality are mediated by a non-canonical IRE1-dependent mechanism. Together, our study provides the first insight into how a disruption of hepatic ER-mediated lipid metabolic regulation promotes sepsis-associated cardiac immuno-metabolic imbalance.

pathology↗

bioRxiv2023

Ubiquinone deficiency drives reverse electron transport to disrupt hepatic metabolic homeostasis in obesity

Mitochondrial reactive oxygen species (mROS) are central to physiology. While excess mROS production has been associated with several disease states, its precise sources, regulation, and mechanism of generation in vivo remain unknown, limiting translational efforts. Here we show that in obesity, hepatic ubiquinone (Q) synthesis is impaired, which raises the QH2/Q ratio, driving excessive mROS production via reverse electron transport (RET) from site IQ in complex I. Using multiple complementary genetic and pharmacological models in vivo we demonstrated that RET is critical for metabolic health. In patients with steatosis, the hepatic Q biosynthetic program is also suppressed, and the QH2/Q ratio positively correlates with disease severity. Our data identify a highly selective mechanism for pathological mROS production in obesity, which can be targeted to protect metabolic homeostasis.

biochemistry↗

bioRxiv2022

Endothelial FABP4 constitutes the majority of basal circulating hormone levels and regulates lipolysis-driven insulin secretion

Fatty acid binding protein 4 (FABP4) is a lipid chaperone secreted from adipocytes upon stimulation of lipolysis. Circulating FABP4 levels strongly correlate with body mass index and obesity-related pathologies in experimental models and humans. While adipocytes have been presumed to be the major source of hormonal FABP4, this question has not been addressed definitively in vivo. We generated mice with FABP4 deletion in cells known to express the gene; adipocytes (Adipo-KO), endothelial cells (Endo-KO), myeloid cells (Myeloid-KO), and the whole body (Total-KO) to examine the contribution of these cell types to basal and stimulated plasma FABP4 levels. Unexpectedly, baseline plasma FABP4 was only reduced by [~]25% in Adipo-KO mice, whereas Endo-KO mice showed [~]75% decreases compared to wildtype controls. In contrast, Adipo-KO mice exhibited [~]62% reduction in FABP4 responses to lipolysis, while there was minimal reduction in Endo-KO mice, indicating that adipocytes are the main FABP4 source in lipolysis. We did not detect any myeloid cell contribution to circulating FABP4. Surprisingly, despite the nearly intact FABP4 responses, Endo-KO mice showed blunted lipolysis-induced insulin secretion, identical to Total-KO mice. We conclude that the endothelium is the major source of baseline hormonal FABP4 and is required for the insulin response to lipolysis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/511807v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1b2d566org.highwire.dtl.DTLVardef@1d82083org.highwire.dtl.DTLVardef@3e9726org.highwire.dtl.DTLVardef@1357648_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2022

ATGL is differentially required for adipocyte FABP4 secretion in vivo and ex vivo

Fatty acid binding protein 4 (FABP4) is linked with the pathogenesis of metabolic diseases, including diabetes and cardiovascular disease in both mice and humans. It has also been demonstrated that the levels of hormonal FABP4 are strongly associated with obesity, and secretion is stimulated under conditions of fasting and lipolysis both in vivo and in vitro. Here, we utilized adipocyte-specific deficiency of adipose triglyceride lipase (ATGL) in a mouse model (ATGLAdpKO) to evaluate the regulation of FABP4 secretion by lipolytic signals in the absence of actual lipolysis in vivo. Previously, lipolysis-induced FABP4 secretion was found to be significantly reduced upon pharmacological inhibition of ATGL, and from adipose tissue explants from ATGLAdpKO mice. Unexpectedly, upon activation beta-adrenergic receptors, ATGLAdpKO mice exhibited significantly higher levels of circulating FABP4 as compared to ATGLfl/fl controls in vivo, with no corresponding increase in non-esterified free fatty acids or glycerol, confirming the lack of lipolysis. We also generated an additional model with adipocyte-specific deletion of FABP4 in the background of ATGLAdpKO mice (ATGL/FABP4AdpKO or DKO) to evaluate the cellular source of circulating FABP4. In these animals, there was no evidence of lipolysis-induced FABP4 secretion, indicating that the elevated FABP4 hormone levels in the ATGLAdpKO mice were indeed from the adipocytes. ATGLAdpKO mice did not exhibit an increase in insulin secretion upon stimulation of lipolysis, but had a normal insulin response to glucose injection along with increased FABP4 secretion, suggesting the elevated FABP4 secretion is not due to lack of insulin. Inhibition of sympathetic signaling during lipolysis using hexamethonium significantly reduced FABP4 secretion in ATGLAdpKO mice compared to controls. Therefore, activity of a key enzymatic step of lipolysis mediated by ATGL, per se, is not required for stimulated in vivo FABP4 secretion from adipocytes, which can be induced through sympathetic signaling.

physiology↗

bioRxiv2020

High resolution 3D imaging of liver reveals a central role for subcellular architectural organization in metabolism

Cells display complex intracellular organization through compartmentalization of metabolic processes into organelles, yet neither the resolution of these structures in the native tissue context nor its functional consequences are well understood. Here, we resolved the 3-dimensional organelle structural organization in large (>2.8x105m3) volumes of intact liver tissue (15 partial or full hepatocytes per condition) in high resolution (8nm isotropic pixel size) by utilizing enhanced Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) imaging, followed by deep-learning-based image segmentation and 3D reconstruction. We also performed a comparative analysis of subcellular structures in liver tissue of lean and obese animals and found marked alterations particularly in hepatic endoplasmic reticulum (ER), which undergoes massive structural re-organization in obesity characterized by marked disorganization of stacks of ER sheets and predominance of ER tubules. Finally, we demonstrated the functional importance of these structural changes upon experimental recovery of the subcellular organization and its marked impact on cellular and systemic metabolism. We conclude that hepatic subcellular organization and ERs architecture is highly dynamic, integrated with the metabolic state, and critical for adaptive homeostasis and tissue health.

cell biology↗

bioRxiv2020

Aberrant Ca2+ homeostasis in adipocytes links inflammation to metabolic dysregulation in obesity

Chronic metabolic inflammation is a key feature of obesity, insulin resistance and diabetes, although the initiation and propagation mechanisms of metaflammation are not fully established, particularly in the adipose tissue. Here we show that in adipocytes, altered regulation of the Ca2+ channel inositol triphosphate receptor (IP3Rs) is a key, adipocyte-intrinsic, event involved in the emergence and propagation of inflammatory signaling and the resulting insulin resistance. Inflammation, either induced by cytokine exposure in vitro or by obesity in vivo lead to increased expression and activity of IP3Rs in adipocytes in a JNK-dependent manner. This results in increased cytosolic Ca2+ and impaired insulin action. In mice, adipocyte-specific loss of IP3R1/2 protected against adipose tissue inflammation and insulin resistance despite significant diet-induced weight gain. Thus, this work reveals that IP3R over-activation and the resulting increase in cytosolic Ca2+ is a key link between obesity, inflammation and insulin resistance, and suggests that approaches to target adipocyte Ca2+ homeostasis may offer new therapeutic opportunities against metabolic diseases, especially since GWAS studies also implicate this locus in human obesity.

physiology↗

bioRxiv2020

An unexpected lack of difference in superoxide/H2O2 production rates in isolated heart and skeletal muscle mitochondria from a mouse model of Barth Syndrome

Barth Syndrome (BTHS) is a rare X-linked genetic disorder caused by mutations in tafazzin and characterized by loss of cardiolipin and severe cardiomyopathy. Mitochondrial superoxide/H2O2 production has been implicated in the cardiomyopathy observed in different BTHS models. There are at least 11 mitochondrial sites that produce superoxide/H2O2 at significant rates. Which of these sites generate oxidants at excessive rates in BTHS is unknown. Here, we measured the maximum capacity of superoxide/H2O2 production from each site in mitochondria isolated from heart and skeletal muscle of the tafazzin knockdown mice (tazkd) at 3, 7 and 12 months of age. Strikingly, the superoxide/H2O2 production capacities of these sites were overall indistinguishable between tazkd mice and their wildtype littermates across the time points analyzed. The only exception was site GQ in glycerol phosphate dehydrogenase, which was increased in the skeletal muscle of 7 months old tazkd mice. Mitochondrial superoxide/H2O2 production was also measured ex vivo during the oxidation of a complex mixture of substrates mimicking either heart or skeletal muscle cytosol and was found to be indistinguishable between wildtype and tazkd mice. However, we consistently measured decreased FAD-linked respiration in mitochondria isolated from tazkd mice. We conclude that the maximum capacity and ex vivo rates of superoxide/H2O2 production were not increased in mitochondria isolated from heart and skeletal muscle of tazkd mice, despite reduced oxidative capacity. Therefore, it seems unlikely that mitochondrial oxidants contribute to the development of cardiomyopathy in tazkd mice. These observations raise questions about the involvement of mitochondrial oxidants in BTHS pathology.

biochemistry↗