Inflammation is a pivotal driver of the progression from metabolic dysfunction-associated steatotic liver disease (MASLD) to metabolic dysfunction-associated steatohepatitis (MASH), an aggressive form associated with substantial liver-related mortality. However, the molecular mechanisms underlying the initiation and persistence of liver inflammation remain poorly defined. Here, we demonstrated a previously unrecognized role for hepatic acetyl-CoA synthetase short-chain family member 2 (ACSS2) in MASH, showing that ACSS2 upregulation in patients exacerbates MASH progression by functioning as an epigenetic regulator, independent of its canonical lipogenic role. Mechanistically, ACSS2, in complex with lysine acetyltransferase 5 (KAT5), upregulates allograft inflammatory factor-1 (AIF1) transcription via histone crotonylation, thereby inducing liver inflammation and subsequently resulting in the aberrant accumulation of senescent hepatocytes, which further enhances proinflammatory cytokine production. This ultimately initiates a vicious cycle of chronic inflammation, which directly promotes the progression from simple steatosis to MASH. Thus, our work reveals a mechanistically defined and pivotal role for ACSS2 in promoting the MASLD-to-MASH transition, highlighting its potential as a compelling therapeutic target.

Adiponectin signaling is essential for hepatic glucose homeostasis, yet the molecular basis of adiponectin receptor responsiveness remains incompletely understood. Here, we identify the Nogo-B receptor (NgBR; NUS1) as a regulator of hepatic adiponectin sensitivity. Across human, cynomolgus monkey, and mouse datasets, hepatic NgBR expression is consistently reduced in obesity-associated diabetes, indicating a conserved metabolic signature. Hepatocyte-specific NgBR deletion abolishes the metabolic effects of the adiponectin agonist AdipoRon, resulting in impaired AMPK activation, persistent gluconeogenesis, and ceramide accumulation. Mechanistically, NgBR loss suppresses KAT7 expression and reduces histone acetylation at AdipoR1 and AdipoR2 promoters, thereby limiting receptor expression. Adeno-associated virus (AAV)-mediated restoration of hepatic NgBR reinstates KAT7-dependent chromatin activation, adiponectin receptor expression, and glucose homeostasis. These findings support a hepatocellular mechanism in which NgBR maintains adiponectin receptor competence and suggest a potential therapeutic strategy for restoring adiponectin responsiveness in metabolic disease.

Abstract Somatic mutations in CREB binding protein (CREBBP or CBP), which encodes a histone acetyltransferase, are frequently observed in cancers such as lymphoma and non-small cell lung cancer. Here, we report that CREBBP loss-of-function (LOF) mutations lead to the deacetylation of histone deacetylase 3 (HDAC3) and promote cancer cell growth by transcriptional silencing of the tumor suppressor gene phosphatase and tensin homolog (PTEN). Mechanistically, we found that CBP specifically binds to HDAC3 and acetylates it at a previously unknown residue, which is necessary for reducing HDAC3 activity and increasing histone acetylation. Additionally, our data show that HDAC3 acetylation is crucial for maintaining PTEN expression via acetylated histone-regulated transcription. The loss of HDAC3 acetylation in cancers with CBP LOF mutations results in PTEN deficiency, thereby promoting tumor development and resistance to chemotherapy. Our findings reveal a novel epigenetic mechanism regulating PTEN expression and suggest that HDAC3 could be a potential alternative target for cancers with CBP LOF mutations.To our knowledge, this is the first report of the previously unrecognized acetylation of HDAC3, a critical deacetylase involved in cancer. This discovery is significant because our data show that HDAC3 acetylation is essential for regulating its activity by disrupting the CK2a-mediated phosphorylation of HDAC3. We clarify that HDAC3 acetylation is controlled by the acetyltransferase CBP and the deacetylase Sirt1. The key finding is the connection between HDAC3 acetylation and PTEN loss in CBP mutant cancers. Our data also link HDAC3 acetylation to cancer patient survival and suggest that targeting HDAC3 could help restore the tumor suppressor PTEN in cancers with CBP LOF mutations. Our results provide a new understanding of the epigenetic regulation of PTEN in tumor development. Citation Format: Xiang Wang, Wenquan Hu, Qing Robert Miao. CREBBP mutation promotes tumor growth by impairing HDAC3 acetylation-dependent expression of PTEN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 597.

Acetate is the end product of alcohol metabolism. Acyl-CoA synthetase short-chain family member 2 (ACSS2) converts acetate to acetyl-CoA, involving metabolic pathways and epigenetic regulation. However, the function of ACSS2-mediated epigenetic control in alcoholic liver disease (ALD) remains incompletely understood. We demonstrate that alcohol downregulates hepatic ACSS2, causing acetate accumulation in the liver and serum. This disrupts iron metabolism and hepatic ferroptosis, triggering liver injury and inflammation. Mechanistically, ACSS2 binds CREB binding protein (CBP) to mediate histone acetylation and regulate hepcidin antimicrobial peptide 1/2 (HAMP1/2) transcription. ACSS2 deficiency downregulates HAMP1/2, causing systemic iron dyshomeostasis and ferroptosis, which is restored by overexpression of HAMP1/2. Iron chelators or ferroptosis inhibitors attenuates alcohol-induced liver injury in ACSS2-deficient mice. Our study uncovers the epigenetic mechanisms of ACSS2-mediated ferroptosis and its role in ALD progression.

MYCN amplification, a characteristic of aggressive neuroblastoma, presents therapeutic challenges. This study uncovered the potential effects of a fructose metabolite, acetate, on the transcriptional regulation of MYCN expression, which is still largely unexplored. We elucidated the pivotal role of acyl-coenzyme A (acyl-CoA) synthetase short-chain family member 2 (ACSS2), found to be heightened in MYCN-amplified neuroblastoma. We demonstrated that ACSS2 enhanced MYCN gene transcription and growth of MYCN-amplified neuroblastoma. Our results revealed a new mechanism wherein ACSS2 orchestrates MYCN transcription by escalating acetyl-CoA levels and histone acetylation, hinting at a metabolic participation in forcibly dictating MYCN regulation. We further demonstrated that fructose or acetate exacerbated neuroblastoma growth, which can be halted by the ACSS2 inhibitor. We further identified the Nogo-B receptor (NgBR) as the trigger for ACSS2 induction through the Akt-SREBP-1 pathway. Our findings propose NgBR as a novel therapeutic target, emphasizing the promising potential of metabolic therapies for managing aggressive MYCN-amplified neuroblastoma.

Patients with diabetes are prone to developing cerebrovascular disease (CVD) due to a multitude of factors. Particularly, the hyperglycemic environment is a key contributor to the progression of diabetes-associated complications. However, there is a dearth of knowledge regarding glucose transporter 1 (GLUT1, also known as SLC2A1)-dependent mechanisms responsible for these adverse effects. Here, we revealed the importance of glucose transporter 1 in preserving brain endothelial cell homeostasis beyond regulating glucose uptake. To elucidate the GLUT1-mediated protective mechanism, we used bulk RNA sequencing (RNA-Seq) to analyze the transcriptomic alterations under hyperglycemia and GLUT1-deficient conditions and validated the critical gene changes in cultured human brain endothelial cells and diabetic mouse models. We found that GLUT1 downregulation is linked to increased expression levels of podocalyxin (PODXL) and decreased thioredoxin-interacting protein (TXNIP) within healthy brain endothelial cells incubated with high glucose, demonstrating an antistress response mechanism. Interestingly, brain endothelial cells isolated from diabetic mice no longer showed a similar protection mechanism. Instead, the diabetic endothelial cells are characterized by considerably enriched GLUT1 and TXNIP expression under a hyperglycemic state. GLUT1 overexpression recaptures the diabetic features, such as elevated expression of TXNIP and NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, along with increased IL-1β production and permeability. Our findings of a GLUT1-dependent regulatory mechanism for the endothelium provide a potentially deeper insight into mechanistic shifts that occur due to the diabetic disease state and the pathogenesis of diabetes-associated vascular complications.NEW & NOTEWORTHY Glucose transporter-1 is known for regulating glucose uptake in brain endothelial cells. This study used global transcriptome analysis and diabetic mouse models to reveal the novel role of glucose transporter 1 in regulating brain endothelial cell homeostasis by reducing the inflammation response and increasing the protection mechanism. Importantly, the glucose transporter 1-dependent protection mechanism is compromised in diabetic conditions, which explains why patients with diabetes have a high risk of cerebrovascular diseases.

Obesity is a well-known risk factor for type 2 diabetes (T2D), with over 90% of T2D patients being overweight or obese. However, only approximately 30% of obese individuals develop T2D, suggesting the existence of resilience factors in non-T2D obese individuals that protect against obesity-related T2D. Our research aimed to identify these protective factors by comparing gene expression profiles between obese T2D patients and obese individuals without T2D. Our findings suggest that the Nogo-B receptor (NgBR) may be a key resilience factor in preventing obesity-induced T2D. We observed that obesity-induced loss of NgBR in the liver disrupts the regulation of hepatic gluconeogenesis and insulin sensitivity. This was further supported by decreased NgBR expression in the livers of diabetic mice and T2D obese patients, compared to non-T2D obese and lean subjects. NgBR hepatocyte-specific knockout mice exhibited a moderate increase in blood glucose levels, which was significantly augmented by high-fat diet (HFD) feeding to T2D levels. Our data demonstrated that NgBR plays a crucial, previously unrecognized role in maintaining AMPK activation. NgBR binds to the farnesylated form of liver kinase B1 (LKB1), a key regulator of AMPK. The depletion of NgBR in hepatocytes disrupts the localization of LKB1 in the plasma membrane, impairing AMPK activation, a critical signal for adiponectin-mediated insulin sensitivity. The loss of NgBR in the obese liver disrupts adiponectin-dependent regulation of hepatic gluconeogenesis and insulin sensitivity. NgBR hepatocyte-specific knockout mice display many prediabetes characteristics and are more susceptible to HFD-induced T2D onset. In conclusion, our findings indicate that NgBR is a critical resilience factor necessary for maintaining hepatic gluconeogenesis regulation and preventing insulin resistance in obesity-associated T2D. Disclosure M. Mohiuddin: None. W. Hu: None. R. Barua: None. M.B. Tirumalasetty: None. M. Choubey: None. Q. Miao: None. Funding NIDDK (DK132056, DK112971)

The COVID-19 pandemic has underlined the link between cytokine storms and acute lung injury (ALI). Importantly, diabetic patients demonstrate a higher susceptibility to severe lung injury and increased mortality, indicating that hyperglycemia could compromise the host's resilience necessary to counteract cytokine-induced lung injury. Single-nucleus RNA-seq data from COVID-19 patients reveal a significant decline in endothelial cells expressing the Nogo-B receptor (NgBR). Our recent research confirms that NgBR plays a pivotal role in maintaining the structural integrity of blood vessels by regulating KAT7-mediated histone acetylation.To investigate NgBR's resilience role, we examined its expression in response to hyperglycemic stress. We found a reduction in NgBR expression levels in endothelial cells (ECs) isolated from db/db mice, mirroring observations in ECs from Streptozocin (STZ)-injected mice. Moreover, when human microvascular endothelial cells (HMECs) were exposed to high glucose levels, NgBR expression increased initially but subsequently declined with extended exposure. This inhibitory effect of high glucose on NgBR expression was both time- and dose-dependent and was mediated through the DNA methylation mechanism.We also examined the effects of NgBR loss on the integrity of pulmonary vasculature and the pathogenesis of lung injury. We induced genetic depletion of NgBR in ECs through tamoxifen administration and found severe lung hemorrhage in NgBR inducible endothelial cell-specific knockout (iecKO) mice. Impaired EC junctions were identified by reduced VE-cadherin immunostaining. Following exposure to a lipopolysaccharide (LPS), ALI model, we observed increased neutrophil accumulation in the alveolar or interstitial space, alveolar wall thickening, and edema in the lungs of either NgBR iecKO or diabetic mice. RNA-seq analysis revealed that NgBR knockdown resulted in decreased transcription of CDC42, a key gene regulating endothelial adherens junction through KAT7-mediated histone acetylation. Our findings indicate that NgBR is a resilience factor for maintaining vascular integrity, and epigenetic medicine can rescue NgBR loss in endothelial cells and the severity of diabetes-associated acute lung injury.

Nonalcoholic fatty liver diseases ( NALFD) are associated with high cardiovascular disease ( CVD ) risk. The demand for novel CVD treatments leads to the recent discovery of the Proprotein Convertase Subtilisin Kexin 9 ( PCSK9 ), which promotes the degradation of low-density lipoprotein receptor ( LDLR ) to increase atherogenic lipoprotein LDL cholesterol ( LDL-C ) levels. Targeting PCSK9 shows promising benefits in mitigating CVD and NAFLD. However, the underlying mechanism causing the NAFLD-associated PCSK9 induction is still unclear. Our findings fill the critical knowledge gap by elucidating that Retinoid X Receptor alpha ( RXRα ) is essential to regulate the transcription of PCSK9 in the liver. Our preliminary data showed that hepatic depletion of RXRα leads to hepatic steatosis. To reveal the underlying mechanism by which hepatic RXRα deficiency promotes NAFLD development, we carried out the RNA-seq analysis. The Gene Set Enrichment Analysis ( GSEA ) of RNA-seq data showed the expected downregulation of PPARα signaling genes and the unexpected upregulation of cholesterol pathway genes in the liver of RXRα hepatocyte-specific knockout ( hepKO ) mice. One of the significantly upregulated genes in the cholesterol pathway is PCSK9, which induction in the liver of RXRα hepKO mice can be abolished by AAV8-mediated overexpression of RXRα. Consistently, we observed the increased cholesterol and LDL-C in the plasma of RXRα hepKO mice, and hepatic overexpression of RXRα can significantly reduce the plasma cholesterol and LDL-C levels. Recently, we identified a previously unrecognized acetylation residue of RXRα, which controls the heterodimerization between RXRα and PPARα. The inhibitory effects of constitutively acetylated RXRα mutant further indicate that acetylation of RXRα is essential for preventing the induction of PCSK9 in the liver of RXRα hepKO mice. Interestingly, we also observed the decreased acetylation of RXRα in the liver of high-fat diet ( HFD )-fed mice and human NAFLD patients. These results suggest that RXRα acetylation is required for regulating the PPARα-mediated repression of PCSK9 transcription in the liver, and impaired RXRα acetylation in the NAFLD liver results in increased PCSK9 and atherosclerosis risk.

Background: Hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) is a risk factor for atherosclerosis. Nogo-B receptor (NgBR) plays important roles in hepatic steatosis and cholesterol transport. However, the effect of NgBR overexpression on atherosclerosis remains unknown. Materials and Methods: Apolipoprotein E deficient (ApoE-/-) mice infected with adeno-associated virus (AAV)-NgBR expression vector were fed a high-fat diet for 12 weeks, followed by determination of atherosclerosis and the involved mechanisms. Results: We determined that high expression of NgBR by AAV injection mainly occurs in the liver and it can substantially inhibit en face and aortic root sinus lesions. NgBR overexpression also reduced levels of inflammatory factors in the aortic root and serum, and levels of cholesterol, triglyceride, and free fatty acids in the liver and serum. Mechanistically, NgBR overexpression increased the expression of scavenger receptor type BI and the genes for bile acid synthesis, and decreased the expression of cholesterol synthesis genes by reducing sterol regulatory element-binding protein 2 maturation in the liver, thereby reducing hypercholesterolemia. In addition, NgBR overexpression activated AMP-activated protein kinase α via the Ca2+ signaling pathway, which inhibited fat synthesis and improved hypertriglyceridemia. Conclusions: Taken together, our study demonstrates that overexpression of NgBR enhanced cholesterol metabolism and inhibited cholesterol/fatty acid synthesis to reduce hyperlipidemia, and reduced vascular inflammation, thereby inhibiting atherosclerosis in ApoE-/- mice. Our study indicates that NgBR might be a potential target for atherosclerosis treatment.

Increased Nogo-B receptor (NGBR) expression in the liver improves insulin sensitivity by reducing endoplasmic reticulum stress (ER stress) and activating the AMPK pathway, although it remains elusive the mechanisms by which NGBR is induced. In this study, we found that PPARγ ligands (rosiglitazone or pioglitazone) increased NGBR expression in hepatic cells and HUVECs. Furthermore, promoter analysis defined two PPREs (PPARγ-responsive elements) in the promoter region of NGBR, which was further confirmed by the ChIP assay. In vivo, using liver-specific PPARγ deficient (PPARγLKO) mice, we identified the key role of PPARγ expression in pioglitazone-induced NGBR expression. Meanwhile, the basal level of ER stress and inflammation was slightly increased by NGBR knockdown. However, the inhibitory effect of rosiglitazone on inflammation was abolished while rosiglitazone-inhibited ER stress was weakened by NGBR knockdown. Taken together, these findings show that NGBR is a previously unrecognized target of PPARγ activation and plays an essential role in PPARγ-reduced ER stress and inflammation.

Cerebral cavernous malformations (CCMs) are enlarged leaking vascular lesions in the brain caused by loss-of-function mutations in CCM1/2/3 genes or loss of expression. Although we previously showed that Nogo-B receptor (NgBR) knockout in endothelial cells (ECs) results in CCMs-like cerebrovascular lesions in the mouse embryo, the molecular mechanism by which NgBR regulates CCM1/2 expression has not been elucidated. Here, we show that temporal genetic depletion of NgBR in ECs at both the postnatal and adult stages results in CCM1/2 expression deficiency and consequently CCMs-like lesions such as enlarged vessels, blood-brain barrier (BBB) hyperpermeability, and intracerebral hemorrhage. These cerebrovascular defects in the brain of NgBR endothelial-specific knockout (ecKO) mice can be rescued by adeno-associated virus (AAV)-mediated overexpression of CCM1 and CCM2 genes. To reveal the molecular mechanism, we used RNA-seq analysis to examine changes in the transcriptome. Surprisingly, we found that acetyltransferase HBO1 was downregulated in NgBR deficient ECs. The mechanistic study elucidated that NgBR is required for maintaining the expression of CCM1/2 in ECs via HBO1-mediated histone acetylation. ChIP-qPCR data further demonstrated that loss of NgBR impairs the binding of both the HBO1 and acetylated H4K5/K12 at the promoter of CCM1 and CCM2 genes. Similarly, AAV-mediated overexpression of HBO1 restores the acetylation of H4K5/K12 and rescues the CCMs-like cerebrovascular defects in the brain of NgBR ecKO mice. Our findings on epigenetic regulation of CCM1 and CCM2 provide a perspective that NgBR and HBO1-mediated histone H4 acetylation may be targeted for preventing the onset of CCMs-like cerebrovascular disease.

The loss function of cerebral cavernous malformation (CCM) genes leads to most CCM lesions characterized by enlarged leaking vascular lesions in the brain. Although we previously showed that NOGOB receptor (NGBR) knockout in endothelial cells (ECs) results in cerebrovascular lesions in the mouse embryo, the molecular mechanism by which NGBR regulates CCM1/2 expression has not been elucidated. Here, we show that genetic depletion of Ngbr in ECs at both postnatal and adult stages results in CCM1/2 expression deficiency and cerebrovascular lesions such as enlarged vessels, blood-brain-barrier hyperpermeability, and cerebral hemorrhage. To reveal the molecular mechanism, we used RNA-sequencing analysis to examine changes in the transcriptome. Surprisingly, we found that the acetyltransferase HBO1 and histone acetylation were downregulated in NGBR-deficient ECs. The mechanistic studies elucidated that NGBR is required for maintaining the expression of CCM1/2 in ECs via HBO1-mediated histone acetylation. ChIP-qPCR data further demonstrated that loss of NGBR impairs the binding of HBO1 and acetylated histone H4K5 and H4K12 on the promotor of the CCM1 and CCM2 genes. Our findings on epigenetic regulation of CCM1 and CCM2 that is modulated by NGBR and HBO1-mediated histone H4 acetylation provide a perspective on the pathogenesis of sporadic CCMs.

Infantile hemangioma is a vascular tumor characterized by the rapid growth of disorganized blood vessels followed by slow spontaneous involution. The underlying molecular mechanisms that regulate hemangioma proliferation and involution still are not well elucidated. Our previous studies reported that NOGOB receptor (NGBR), a transmembrane protein, is required for the translocation of prenylated RAS from the cytosol to the plasma membrane and promotes RAS activation. Here, we show that NGBR was highly expressed in the proliferating phase of infantile hemangioma, but its expression decreased in the involuting phase, suggesting that NGBR may have been involved in regulating the growth of proliferating hemangioma. Moreover, we demonstrate that NGBR knockdown in hemangioma stem cells (HemSCs) attenuated growth factor-stimulated RAS activation and diminished the migration and proliferation of HemSCs, which is consistent with the effects of RAS knockdown in HemSCs. In vivo differentiation assay further shows that NGBR knockdown inhibited blood vessel formation and adipocyte differentiation of HemSCs in immunodeficient mice. Our data suggest that NGBR served as a RAS modulator in controlling the growth and differentiation of HemSCs.

Cerebral cavernous malformations (CCMs) are enlarged leaking vascular lesions in the brain caused by loss-of-function mutations in CCM1/2/3 genes or loss of expression. Although we previously showed that Nogo-B receptor (NgBR) knockout in endothelial cells (ECs) results in CCMs-like cerebrovascular lesions in the mouse embryo, the molecular mechanism by which NgBR regulates CCM1/2 expression has not been elucidated. Here, we show that temporal genetic depletion of NgBR in ECs at both the postnatal and adult stages results in CCM1/2 expression deficiency and consequently CCMs-like lesions such as enlarged vessels, blood-brain barrier (BBB) hyperpermeability, and cerebral hemorrhage. These cerebrovascular defects in the brain of NgBR endothelial-specific knockout (ecKO) mice can be rescued by adeno-associated virus (AAV)-mediated overexpression of CCM1 and CCM2 genes. To reveal the molecular mechanism, we used RNA-seq analysis to examine changes in the transcriptome. Surprisingly, we found that acetyltransferase HBO1 was downregulated in NgBR deficient ECs. The mechanistic study elucidated that NgBR is required for maintaining the expression of CCM1/2 in ECs via HBO1-mediated histone acetylation. ChIP-qPCR data further demonstrated that loss of NgBR impairs the binding of both the HBO1 and acetylated H4K5/K12 at the promoter of CCM1 and CCM2 genes. Similarly, AAV-mediated overexpression of HBO1 restores the acetylation of H4K5/K12 and rescues the CCMs-like cerebrovascular defects in the brain of NgBR ecKO mice. Our findings on epigenetic regulation of CCM1 and CCM2 provide a perspective that NgBR and HBO1-mediated histone H4 acetylation may be targeted for preventing the onset of CCMs-like cerebrovascular disease.

The reduction of insulin resistance or improvement of insulin sensitivity is the most effective treatment for type 2 diabetes (T2D). We previously reported that Nogo-B receptor (NGBR), encoded by the NUS1 gene, is required for attenuating hepatic lipogenesis by blocking nuclear translocation of liver X receptor alpha, suggesting its important role in regulating hepatic lipid metabolism. Herein, we demonstrate that NGBR expression was decreased in the liver of obesity-associated T2D patients and db/db mice. NGBR knockout in mouse hepatocytes resulted in increased blood glucose, insulin resistance, and beta-cell loss. High-fat diet (HFD)/streptozotocin (STZ)-treated mice presented the T2D phenotype by showing increased nonesterified fatty acid (NEFA) and triglyceride (TG) in the liver and plasma and increased insulin resistance and beta-cell loss. AAV-mediated NGBR overexpression in the liver reduced NEFA and TG in the liver and circulation and improved liver functions. Consequently, HFD/STZ-treated mice with hepatic NGBR overexpression had increased insulin sensitivity and reduced beta-cell loss. Mechanistically, NGBR overexpression restored insulin signaling of AMPKα1-dependent phosphorylation of AKT and GSK3β. NGBR overexpression also reduced expression of endoplasmic reticulum stress-associated genes in the liver and skeletal muscle to improve insulin sensitivity. Together, our results reveal that NGBR is required to ameliorate T2D in mice, providing new insight into the role of hepatic NGBR in insulin sensitivity and T2D treatment.

Adiponectin is an adipocyte-secreted protein hormone and prevents the development of insulin resistance. The adiponectin-mediated activation of AMP-activated protein kinase (AMPK) pathway is essential for decreasing the expression of hepatic gluconeogenic enzymes and enhancing the hepatic effects of insulin. However, the resilience factors required to maintain adiponectin-mediated AMPK activation signaling in the liver remain unclear. Recent studies from our laboratory suggest that NgBR plays a previously unrecognized role in preserving AMPK activation. The loss of NgBR in the obesity liver impairs adiponectin-dependent gluconeogenesis and insulin sensitivity. NgBR hepatocyte-specific knockout (hepKO) mice resemble many features of prediabetes, such as moderately increased fasting blood glucose levels and insulin resistance, as well as facilitating the high-fat diet (HFD)-induced onset of T2D. NgBR was identified as a cell surface receptor for soluble Nogo-B (sNogo-B). Also, NgBR binds the farnesylated form of liver kinase B1 (LKB1-farn), a key regulator of AMPK. NgBR depletion in hepatocytes abolishes the localization of LKB1 in the plasma membrane and impairs AMPK activation, the critical signal for adiponectin-mediated insulin sensitivity. NgBR expression is decreased in the liver of diabetic mice. Similar changes also occur in diabetes patients. The NgBR transcript level is reduced in T2D obese patients’ liver compared to non-T2D obese and lean subjects. Additional in vitro studies show that NgBR deficiency in hepatocyte prevents AMPK activation induced by AdipoRon (an agonist of adiponectin receptor) and increases the gluconeogenesis. Our data suggest that NgBR is a potential resilience factor required for preserving adiponectin-mediated insulin sensitivity and preventing the onset of obesity-caused T2D, and disruption of the NgBR-dependent regulation system leads to impairing gluconeogenesis regulation and insulin sensitivity in the liver. Disclosure W. Hu: None. X. Wang: None. Q. Miao: None. Funding National Institutes of Health (R01DK112971)

Endothelial cell (EC), consisting of the innermost cellular layer of all types of vessels, is not only a barrier composer but also performing multiple functions in physiological processes. It actively controls the vascular tone and the extravasation of water, solutes, and macromolecules; modulates circulating immune cells as well as platelet and leukocyte recruitment/adhesion and activation. In addition, EC also tightly keeps coagulation/fibrinolysis balance and plays a major role in angiogenesis. Therefore, endothelial dysfunction contributes to the pathogenesis of many diseases. Growing pieces of evidence suggest that histone protein acetylation, an epigenetic mark, is altered in ECs under different conditions, and the acetylation status change at different lysine sites on histone protein plays a key role in endothelial dysfunction and involved in hyperglycemia, hypertension, inflammatory disease, cancer and so on. In this review, we highlight the importance of histone acetylation in regulating endothelial functions and discuss the roles of histone acetylation across the transcriptional unit of protein-coding genes in ECs under different disease-related pathophysiological processes. Since histone acetylation changes are conserved and reversible, the knowledge of histone acetylation in endothelial function regulation could provide insights to develop epigenetic interventions in preventing or treating endothelial dysfunction-related diseases.