Faculty Bibliography

Long-chain fatty acids in the blood are prevented from unfettered movement into nonfenestrated tissues or the arterial wall. During fasting, nonesterified FAs are released from adipose tissue into the circulation and bind to albumin, forming a complex >65 kDa, with limited ability to efficiently cross endothelial cell (EC) barriers without a specific receptor. For this reason, nonhepatic tissue distribution of circulating FA parallels EC expression of the FA-binding protein CD36 (cluster of differentiation 36). The deletion of CD36 in ECs reduces nonesterified FA uptake by the heart, muscle, and brown adipose tissue. The other major transport system for FAs is via lipoproteins. Circulating FAs are contained within TRLs (triglyceride-rich lipoproteins), chylomicrons during the postprandial period, and VLDL (very low-density lipoprotein) both postprandially and during fasting. LPL (lipoprotein lipase) on capillary ECs releases FAs from TRLs and likely allows their passage into tissues, in part, via a CD36-independent process. ECs can also internalize lipoprotein particles, followed by the transendothelial movement of lipids. In this review, we will discuss the pathways of EC uptake of FAs from circulation, how this process affects both EC and tissue biology, and the importance of these processes for systemic metabolism and vascular health. We will conclude with speculations on methods to modulate EC FA uptake and their implications for human health.

The interaction between sleep, circadian rhythms and cardiovascular resilience is a crucial yet underexplored research area with important public health implications. Disruptions in sleep and circadian rhythms exacerbate hypertension, diabetes mellitus and obesity, conditions that are increasingly prevalent globally and increase the risk of cardiovascular disease. A National Heart, Lung, and Blood Institute workshop examined these connections, as well as the emerging concept of cardiovascular resilience as a dynamic and multifaceted concept spanning molecular, cellular and systemic levels across an individual's lifespan. The workshop emphasized the need to expand the focus from solely understanding whether and how sleep and circadian rhythm disturbances contribute to disease, to also exploring how healthy sleep and aligned circadian rhythms can increase cardiovascular resilience. To develop a Roadmap towards this goal, workshop participants identified key knowledge gaps and research opportunities, including the need to integrate biological, behavioural, environmental and societal factors in sleep and circadian health with cardiovascular research to identify therapeutic targets. Proposed interventions encompass behavioural therapies, chronotherapy, lifestyle changes, organizational policies and public health initiatives aimed at improving sleep and circadian health for better cardiovascular outcomes. Future cross-disciplinary research and translation of discoveries into public health strategies and clinical practices could improve cardiovascular resilience across the lifespan in all populations.

Increased fasting and postprandial triglyceride levels are risk factors for cardiovascular disease (CVD). Partially metabolized triglyceride-rich lipoproteins (TRLs) termed remnants are created when intestinally-derived chylomicrons and liver secreted very low density lipoproteins (VLDLs) interact with lipoprotein lipase (LpL) situated on the luminal surface of capillary endothelial cells. Higher circulating remnant levels have been implicated as the reason for the relationship between TRL levels and CVD. We hypothesized that nascent lipoproteins not only remnants are atherogenic. To test this, we created mice with induced whole-body lipoprotein lipase (LpL) deficiency combined with LDL receptor (LDLR) deficiency. On an atherogenic Western-type diet (WD), male and female mice with induced global LpL deficiency (iLpl^-/-) and LDLR knockdown (Ldlr^kd) developed hypertriglyceridemia and elevated cholesterol levels; all the increased cholesterol was in chylomicrons or large VLDL. After 12 weeks on a WD, atherosclerotic lesions both in the brachiocephalic artery and the aortic root were more severe in iLpl^-/-/Ldlr^kd mice than control Ldlrkd mice. Aorta from hypertriglyceridemic mice had changes in the transcriptomes of endothelial cells, macrophages, and smooth muscle cells indicating vascular inflammation. Our data show that intact TRLs contribute to atherosclerosis, explain the association of postprandial lipemia and vascular disease and prove that non-remnant TRLs are not benign.

BACKGROUND/UNASSIGNED:Movement of circulating lipids into tissues and arteries requires transfer across the endothelial cell (EC) barrier. This process allows the heart to obtain fatty acids, its chief source of energy, and apoB-containing lipoproteins to cross the arterial endothelial barrier, leading to cholesterol accumulation in the subendothelial space. Multiple studies have established elevated postprandial TRLs (triglyceride-rich lipoproteins) as an independent risk factor for cardiovascular disease. We explored how chylomicrons affect ECs and transfer their fatty acids across the EC barrier. METHODS/UNASSIGNED:C]oleate, we studied the uptake and release of this labeled by ECs. RESULTS/UNASSIGNED:]C labeled chylomicron triglycerides exited ECs primarily in phospholipids. EVs from chylomicron-treated versus untreated ECs were larger, more abundant, and contained specific microRNAs. Treatment of macrophages and naive ECs with media from chylomicron-treated ECs increased expression of inflammatory genes. CONCLUSIONS/UNASSIGNED:EC chylomicron metabolism produces EVs that increase macrophage inflammation and create LDs. Media containing these EVs also increases EC inflammation, illustrating an autocrine inflammatory process. Fatty acids within chylomicron triglycerides are converted to phospholipids within EVs. Thus, EC uptake of chylomicrons constitutes an important pathway for vascular inflammation and tissue lipid acquisition.

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.

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.

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.

BACKGROUND:RYGB consists of the Roux limb (RL), the biliopancreatic limb (BPL), and the common channel (CC). There is no consensus on the optimal limb lengths. METHODS:Using a mouse model of RYGB, 30 diet-induced obese mice were divided into two groups with varying BPL and CC lengths: a standard BPL with a long CC (RYGB S) and a long BPL with a short CC (RYGB L). Additionally, 9 age-matched, lean control mice (LC) were also included in this study. RESULTS:RYGB S had limb lengths of RL = 17%, BPL = 24%, and CC = 59%. RYGB L had limb lengths of RL = 17%, BPL = 32%, and CC = 51%. RYGB S and RYGB L had 67% and 40% survival, respectively. Mortality in RYGB L included more instances where the cause of death was not apparent. RYGB L demonstrated greater weight loss, lower energy expenditure, and lower heart mass as compared to RYGB S. Both RYGB groups had lower epidydimal fat mass, spleen mass, and bone mineral density compared to LC. RYGB L had a lower heart mass than RYGB S and LC. While the relative abundance of Eubacterium was lower in RYGB L than in RYGB S, no other gut microbiota differences were observed. CONCLUSIONS:A longer BPL with a shorter CC induces greater weight loss but may lead to adverse effects, including lower heart mass, reduced bone density, and deaths with unclear causes.