Regulation of macrophage immunometabolism in atherosclerosis.

Purpose: Epidemiological data links lack of breastfeeding with increased risk of breast cancer, particularly triple negative breast cancer (TNBC). The involution process is characterized by mammary tissue remodeling, including adipocyte repopulation and re-differentiation fueled by metabolic rewiring. Our mouse model mimicking short-term breast feeding that leads to abrupt involution (AI) revealed a chronic inflammatory state in the mammary gland (MG) (Basree, et al. Breast Cancer Research; 2019). As metabolic dysfunction is linked to increased BC risk, we sought to elucidate the effects of AI and gradual involution (GI) on MG energy metabolism and associated oxidative stress. In addition, we evaluated the impact of AI and GI on whole body glucose metabolism and insulin response/resistance. Methods: FVB/n mice (8week old) were paired for breeding. At partum, dams were randomized to AI or GI cohort and standardized to 6 pups per dam. AI mice had pups removed on postpartum day 7 (d7) to mimic short-term breastfeeding. GI mice had 3 pups removed on day 28 and 31 each to mimic gradual weaning. MGs were harvested on d28, 56, and 120 postpartum. Prior to harvest, mice underwent an echoMRI and insulin tolerance test (ITT). At harvest, mice were fasted for 4 hours, and blood was collected for serum insulin measurement using Ultra-Sensitive Insulin ELISA. Lipid peroxidation (MDA) and DNA adduct formation (8-OHdG), which represent chronic oxidative stress, were measured in MG by ELISA. Whole MG RNA were subjected to affymetrix followed by gene set enrichment analyses (GSEA) and qPCR for target validation. MGs were also subjected to untargeted metabolomics analysis and Mitofuel flex assay to assess substrate dependence by Seahorse Bioanalyzer. Results: GSEA and qPCR revealed enrichment of fatty acid oxidation (FAO) and mitochondrial oxidative phosphorylation (OXPHOS) pathways in AI MGs at d28, further validated by expression of genes (PGC-1α, Cpt-2, Srebp1c, and Chrebp). Metabolites associated with FAO were enriched in AI MGs at d28 and 56. Mitofuel flex assay indicated a significantly higher dependence on FAO in AI MGs. On d56, fasted blood glucose was significantly higher in AI mice with serum insulin and HOMA-IR trending to be higher than in GI mice. Level of 8-OHdG was elevated in AI MGs at d120. AI mice trended to be heavier, have greater body fat, and lower lean mass than GI Mice at d120. Body weight and percent body fat on d120 were positively correlated to MDA concentration in the mammary gland. Conclusion: Our mouse models of AI and GI revealed early MG specific metabolic shift towards increased FAO and OXPHOS that persists over time in AI glands. Similarly, increased oxidative stress and its association with adiposity at d120 indicates continued effect of AI. This change in adiposity, altered systemic glucose metabolism and metabolic shift seen in AI mice may contribute to the higher risk of breast cancer. [K.O. and K.K. are co-first authors.] Citation Format: Kate Ormiston, Kirti Kaul, Neelam Shinde, Allen Zhang, Morgan Bauer, Hee Kyung Kim, Ramesh K. Ganju, Sarmila Majumder, Bhuvaneswari Ramaswamy. Lack of breast feeding may contribute to increased breast cancer risk by altering metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5814.

Alzheimer's disease (AD), the most common form of dementia, is characterized by the progressive loss of neurons and synapses, and by extracellular deposits of amyloid-β (Aβ) as senile plaques, Aβ deposits in the cerebral blood vessels, and intracellular inclusions of hyperphosphorylated tau in the form of neurofibrillary tangles. Several mechanisms contribute to AD development and progression, and increasing epidemiological and molecular evidence suggests a key role of cholesterol in its initiation and progression. Altered cholesterol metabolism and hypercholesterolemia appear to play fundamental roles in amyloid plaque formation and tau hyperphosphorylation. Over the last decade, growing evidence supports the idea that cholesterol oxidation products, known as oxysterols, may be the missing link between altered brain cholesterol metabolism and AD pathogenesis, as their involvement in neurotoxicity, mainly by interacting with Aβ peptides, is reported.

Alzheimer’s disease (AD), the most common neurodegenerative disorder associated with dementia, is typified by the pathological accumulation of amyloid Aβ peptides and neurofibrillary tangles (NFT) within the brain. Considerable evidence indicates that many events contribute to AD progression, including oxidative stress, inflammation, and altered cholesterol metabolism. The brain’s high lipid content makes it particularly vulnerable to oxidative species, with the consequent enhancement of lipid peroxidation and cholesterol oxidation, and the subsequent formation of end products, mainly 4-hydroxynonenal and oxysterols, respectively from the two processes. The chronic inflammatory events observed in the AD brain include activation of microglia and astrocytes, together with enhancement of inflammatory molecule and free radical release. Along with glial cells, neurons themselves have been found to contribute to neuroinflammation in the AD brain, by serving as sources of inflammatory mediators. Oxidative stress is intimately associated with neuroinflammation, and a vicious circle has been found to connect oxidative stress and inflammation in AD. Alongside oxidative stress and inflammation, altered cholesterol metabolism and hypercholesterolemia also significantly contribute to neuronal damage and to progression of AD. Increasing evidence is now consolidating the hypothesis that oxidized cholesterol is the driving force behind the development of AD, and that oxysterols are the link connecting the disease to altered cholesterol metabolism in the brain and hypercholesterolemia; this is because of the ability of oxysterols, unlike cholesterol, to cross the blood brain barrier (BBB). The key role of oxysterols in AD pathogenesis has been strongly supported by research pointing to their involvement in modulating neuroinflammation, Aβ accumulation, and cell death. This review highlights the key role played by cholesterol and oxysterols in the brain in AD pathogenesis.

Recently, we have found that alterations in cellular cholesterol metabolism are involved in promotion of tau phosphorylation (Fan et al. [2001] J. Neurochem. 76: 391-400; Sawamura et al. [2001] J. Biol. Chem. 276:10314-10319). In addition, we have shown that amyloid beta-protein (A beta) promotes cholesterol release to form A beta-lipid particles (Michikawa et al. [2001] J. Neurosci. 21:7226-7235). These lines of evidence inspired us to conduct further studies on whether A beta affects cholesterol metabolism in neurons, which might lead to tau phosphorylation. Here, we report the effect of A beta1-40 on cholesterol metabolism in cultured neurons prepared from rat cerebral cortex. Oligomeric A beta1-40 inhibited cholesterol synthesis and reduced cellular cholesterol levels in a dose- and time-dependent manner, while freshly dissolved A beta had no effect on cholesterol metabolism. However, oligomeric A beta had no effect on the proteolysis of sterol regulatory element binding protein-2 (SREBP-2) or protein synthesis in cultured neurons. Oligomeric A beta did not enhance lactate dehydrogenase (LDH) release from neuronal cells or decrease signals in the cultures reactive to 3,3'-Bis[N,N-bis(carboxymethyl)aminomethyl]fluorescein, hexaacetoxymethyl ester (calcein AM) staining, indicating that A beta used in this experiment did not cause neuronal death during the time course of our experiments. Since alterations in cholesterol metabolism induce tau phosphorylation, our findings that oligomeric A beta alters cellular cholesterol homeostasis may provide new insight into the mechanism underlying the amyloid cascade hypothesis.

Breast cancer is one of the main leading causes of women death. In recent years, attention has been focused on the role of lipoproteins, alterations of cholesterol metabolism and oxidative stress in the molecular mechanism of breast cancer. A role for high density lipoproteins (HDL) has been proposed, in fact, in addition to the role of reverse cholesterol transport (RCT), HDL exert antioxidant and anti-inflammatory properties, modulate intracellular cholesterol homeostasis, signal transduction and proliferation. Low levels of HDL-Cholesterol (HDL-C) have been demonstrated in patients affected by breast cancer and it has been suggested that low levels of HDL-C could represent a risk factor of breast cancer. Contrasting results have been observed by other authors. Recent studies have demonstrated alterations of the activity of some enzymes associated to HDL surface such as Paraoxonase (PON1), Lecithin-Cholesterol Acyltransferase (LCAT) and Phospholipase A2 (PLA2). Higher levels of markers of lipid peroxidation in plasma or serum of patients have also been observed and suggest dysfunctional HDL in breast cancer patients. The review summarizes results on levels of markers of oxidative stress of plasma lipids and on alterations of enzymes associated to HDL in patients affected by breast cancer. The effects of normal and dysfunctional HDL on human breast cancer cells and molecular mechanisms potentially involved will be also reviewed.

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ObjectiveThe aim of the present study was to analyze the effects of an Astaxanthin (ASTX)- rich extract—a powerful antioxidant—obtained from freshwater crustaceans (Dilocarcinus pagei crabs) on liver disturbed lipid metabolism and oxidative stress in rats fed a high-sucrose diet (HSD).MethodsMale Wistar rats were fed for 13 weeks with either: 1—a standard commercial rodent diet (RD), 2—a HSD, 3—a RD plus ASTX, or 4—a HSD plus ASTX. The rats were given orally either ASTX (10 mg/kg body weight/day in sunflower oil) or only the vehicle.ResultsASTX supplementation attenuated liver injury, as reflected by a reduction in steatosis severity and hepatic triglyceride accumulation. This effect appears to be primarily achieved by promoting mitochondrial fatty acid β-oxidation, as suggested by increased hepatic carnitine palmitoyltransferase-1 (CPT-1) activity, without significantly affecting lipogenesis. In addition, ASTX improved intracellular redox status by preventing the increase in hepatic reactive oxygen species (ROS) levels and by promoting a significant increase in the activity of the antioxidant enzymes catalase (CAT) and glutathione S-transferase (GST). ASTX was also able to restore altered GSH levels. Furthermore, ASTX induced an up-regulation of Nrf2 and a down-regulation of p-NFκB p65 protein expression, key transcription factors that govern cellular responses under pro-oxidant and pro-inflammatory conditions.ConclusionThis study suggests that ASTX obtained from the freshwater crustacean D. pagei exerts beneficial effects against altered hepatic lipid metabolism and oxidative stress in HSD-fed rats, positioning this species as a promising novel source of ASTX for functional nutrition strategies.

Metabolite profiles of striped marsh frog (Limnodynastes peronii) larvae exposed to the anti-androgenic fungicides vinclozolin and propiconazole are consistent with altered steroidogenesis and oxidative stress

Cardiovascular disease including diabetic cardiomyopathy (DbCM) represents the leading cause of death in people with diabetes. DbCM is defined as ventricular dysfunction in the absence of underlying vascular diseases and/or hypertension. The known molecular mediators of DbCM are multifactorial, including but not limited to insulin resistance, altered energy metabolism, lipotoxicity, endothelial dysfunction, oxidative stress, apoptosis, and autophagy. FoxO1, a prominent member of forkhead box O transcription factors, is involved in regulating various cellular processes in different tissues. Altered FoxO1 expression and activity have been associated with cardiovascular diseases in diabetic subjects. Herein we provide an overview of the role of FoxO1 in various molecular mediators related to DbCM, such as altered energy metabolism, lipotoxicity, oxidative stress, and cell death. Furthermore, we provide valuable insights into its therapeutic potential by targeting these perturbations to alleviate cardiomyopathy in settings of type 1 and type 2 diabetes.

Our goal was to identify changes in the metabolome in multiple sclerosis (MS) and how vitamin D supplementation alters metabolic profiles in MS patients and healthy controls. We applied global untargeted metabolomics to plasma from a cross-sectional cohort of age- and sex-matched MS patients and controls and a second longitudinal cohort of MS patients and healthy controls who received 5,000 IU cholecalciferol daily for 90 days. We applied partial least squares discriminant analysis, weighted correlation network analysis (WGCNA), and pathway analysis to the metabolomics data. Generalized estimating equations models were used to assess change in WGCNA-identified module scores or metabolite pathways with vitamin D supplementation. Utilizing multiple analytical techniques, we identified metabolic alterations in oxidative stress (γ-glutamyl amino acid, glutathione) and xenobiotic metabolism (benzoate, caffeine) in MS patients compared with healthy controls in the first cohort. In the vitamin D supplementation cohort, we identified two sets of metabolites altered differentially between MS patients and healthy controls with vitamin D supplementation. The first included markers of oxidative stress and protein oxidation (P = 0.006), while the second contained lysolipids and fatty acids (P = 0.03). Using metabolomics, we identified alterations in oxidative stress and xenobiotic metabolism in MS patients and subsequently demonstrated a reduction of oxidative stress markers with vitamin D supplementation in healthy controls but not in MS patients. We demonstrate the utility of metabolomics in identifying aberrant metabolic processes and in monitoring the ability of therapeutic interventions to correct these abnormalities. ClinicalTrials.gov NCT01667796. This study was supported by NIH grant K23 NS067055, grants from the Race to Erase MS, the National Multiple Sclerosis Society, the American Academy of Neurology, and North American Research Committee on Multiple Sclerosis.

TARGETING ABERRANT CHOLESTEROL METABOLISM IN ALZHEIMER’S DISEASE: DRUG DISCOVERY IN IPSC-DERIVED NEURONS

Heterozygous loss-of-function mutation in TBX5 causes dysregulation of energy metabolism, mitochondrial metabolic pathways and cholesterol metabolism disturbing cardiomyocyte cell physiology

The value of positron emission tomography scanning in the detection of subclinical metastatic melanoma

The contribution of cholesterol and epigenetic changes to the pathophysiology of breast cancer

Neonatal encephalopathy (NE) results from impaired cerebral blood flow and oxygen delivery to the brain. The pathophysiology of NE is complex and our understanding of its underlying pathways continues to evolve. There is considerable evidence that cholesterol dysregulation is involved in several adult diseases, including traumatic brain injury, stroke, Huntington's disease, and Parkinson's disease. Although the research is less robust in pediatrics, there is emerging evidence that aberrations in cholesterol metabolism may also be involved in the pathophysiology of neonatal NE. This narrative review provides an overview of cholesterol metabolism in the brain along with several examples from the adult literature where pathologic alterations in cholesterol metabolism have been associated with inflammatory and ischemic brain injury. Using those data as a background, the review then discusses the current preclinical data supporting the involvement of cholesterol in the pathogenesis of NE as well as how brain-specific cholesterol metabolites may serve as serum biomarkers for brain injury. Lastly, we review the potential for using the cholesterol metabolic pathways as therapeutic targets. Further investigation of the shifts in cholesterol synthesis and metabolism after hypoxia-ischemia may prove vital in understanding NE pathophysiology as well as providing opportunities for rapid diagnosis and therapeutic interventions. IMPACT: This review summarizes emerging evidence that aberrations in cholesterol metabolism may be involved in the pathophysiology of NE. Using data from NE as well as analogous adult disease states, this article reviews the potential for using cholesterol pathways as targets for developing novel therapeutic interventions and using cholesterol metabolites as biomarkers for injury. When possible, gaps in the current literature were identified to aid in the development of future studies to further investigate the interactions between cholesterol pathways and NE.