Potential for Dietary ω-3 Fatty Acids to Prevent Nonalcoholic Fatty Liver Disease and Reduce the Risk of Primary Liver Cancer

Nonalcoholic fatty liver disease (NAFLD) has increased in parallel with central obesity and its prevalence is anticipated to increase as the obesity epidemic remains unabated. NAFLD is now the most common cause of chronic liver disease in developed countries and is defined as excessive lipid accumulation in the liver, i.e., hepatosteatosis. NAFLD ranges in severity from benign fatty liver to nonalcoholic steatohepatitis (NASH), where NASH is characterized by hepatic injury, inflammation, oxidative stress and fibrosis. NASH can progress to cirrhosis; and cirrhosis is a risk factor for primary hepatocellular carcinoma (HCC). The prevention of NASH will lower the risk of cirrhosis and NASH-associated HCC. Our studies have focused on NASH prevention. We developed a model of NASH using Ldlr[superscript -/-] mice fed the western diet (WD). The WD induces a NASH phenotype in these mice that is similar to that seen in humans; and includes robust induction of hepatic steatosis, inflammation, oxidative stress and fibrosis. Using transcriptomic, lipidomic and metabolomic approaches, we examined the capacity of 2 dietary ω3 polyunsaturated fatty acids, eicosapentaenoic acid (20:5ω-3; EPA) and docosahexaenoic acid (22:6ω-3; DHA), to prevent WD-induced NASH. Dietary DHA was superior to EPA at attenuating WD-induced changes in plasma lipids and hepatic injury; and reversing WD effects on hepatic metabolism, oxidative stress, and fibrosis. The outcome of these studies suggests that DHA may be useful in the prevention of NASH and reducing the risk of HCC.This article is a review from the SPLIT D—Surrogate Markers for Cancer Intervention Trials Session presented at the American Institute for Cancer Research (AICR) Conference on Food, Nutrition, Physical Activity and Cancer held 29–31 October 2014 in Washington, DC.Keywords: inflammation, liver cancer, oxidative stress, metabolomics, fibrosis, ω-3 PUFAs, fatty liver diseas

Impact of Sleep and Circadian Disruption on Energy Balance and Diabetes: A Summary of Workshop Discussions

A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact of sleep/circadian disruption in humans to move beyond measurements of insulin and glucose and conduct more in-depth phenotyping. There is also a need for the assessments of sleep and circadian rhythms as well as assessments for sleep-disordered breathing to be incorporated into all ongoing cohort studies related to diabetes risk. Studies in humans need to complement the elegant short-term laboratory-based human studies of simulated short sleep and shift work etc. with studies in subjects in the general population with these disorders. It is conceivable that chronic adaptations occur, and if so, the mechanisms by which they occur needs to be identified and understood. Particular areas of opportunity that are ready for translation are studies to address whether CPAP treatment of patients with pre-diabetes and obstructive sleep apnea (OSA) prevents or delays the onset of diabetes and whether temporal restricted feeding has the same impact on obesity rates in humans as it does in mice

A Metabolomic Analysis of Omega-3 Fatty Acid-Mediated Attenuation of Western Diet-Induced Nonalcoholic Steatohepatitis in LDLR[superscript -/-] Mice

Background: Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease and a risk factor for cirrhosis, hepatocellular carcinoma and liver failure. Previously, we reported that dietary docosahexaenoic acid (DHA, 22:6,n-3) was more effective than eicosapentaenoic acid (EPA, 20:5,n-3) at reversing western diet (WD) induced NASH in LDLR-/- mice. Methods: Using livers from our previous study, we carried out a global non-targeted metabolomic approach to quantify diet-induced changes in hepatic metabolism. Results: Livers from WD + olive oil (WD + O)-fed mice displayed histological and gene expression features consistent with NASH. The metabolomic analysis of 320 metabolites established that the WD and n-3 polyunsaturated fatty acid (PUFA) supplementation had broad effects on all major metabolic pathways. Livers from WD + O-fed mice were enriched in saturated (SFA) and monounsaturated fatty acids (MUFA), palmitoylsphingomyelin, cholesterol, n-6 PUFA, n-6 PUFA-containing phosphoglycerolipids, n-6 PUFA-derived oxidized lipids (12-HETE) and depleted of C20-22 n-3 PUFA-containing phosphoglycerolipids, C20-22 n-3 PUFA-derived oxidized lipids (18-HEPE, 17,18-DiHETE) and S-lactoylglutathione, a methylglyoxal detoxification product. WD + DHA was more effective than WD + EPA at attenuating WD + O-induced changes in NASH gene expression markers, n-6 PUFA and oxidized lipids, citrate and S-lactosyl glutathione. Diet-induced changes in hepatic MUFA and sphingolipid content were associated with changes in expression of enzymes involved in MUFA and sphingolipid synthesis. Changes in hepatic oxidized fatty acids and S-lactoylglutathione, however, correlated with hepatic n-3 and n-6 C20-22 PUFA content. Hepatic C20-22 n-3 PUFA content was inversely associated with hepatic α-tocopherol and ascorbate content and positively associated with urinary F2- and F3-isoprostanes, revealing diet effects on whole body oxidative stress. Conclusion: DHA regulation of hepatic SFA, MUFA, PUFA, sphingomyelin, PUFA-derived oxidized lipids and Slactoylglutathione may explain the protective effects of DHA against WD-induced NASH in LDLR-/- mice

JumpDonaldPublicHealthHumanSciencesOmega-3FattyAcid(Figures1-4).pptx

Epidemiological studies on Greenland Inuits in the 1970s and subsequent human studies have established an inverse relationship between the ingestion of omega-3 fatty acids [C₂₀₋₂₂ ω3 polyunsaturated fatty acids (PUFA)], blood levels of C₂₀₋₂₂ ω3 PUFA and mortality associated with cardiovascular disease [CVD]. C₂₀₋₂₂ ω3 PUFA have pleiotropic effects on cell function and regulate multiple pathways controlling blood lipids, inflammatory factors and cellular events in cardiomyocytes and vascular endothelial cells. The hypolipemic, anti-inflammatory, anti-arrhythmic properties of these fatty acids confer cardioprotection. Accordingly, national heart associations and government agencies have recommended increased consumption of fatty fish or ω3 PUFA supplements to prevent CVD. In addition to fatty fish, additional sources of ω3 PUFA are available from plants, algae and yeast. A key question examined in this review is whether non-fish sources of ω3 PUFA are as effective as fatty fish-derived C₂₀₋₂₂ ω3 PUFA at managing risk factors linked to CVD. We have focused on ω3 PUFA metabolism and the capacity of ω3 PUFA supplements to regulate key cellular events linked to CVD. The outcome of our analysis reveals that non-fish sources of ω3 PUFA vary in their capacity to regulate blood levels of C₂₀₋₂₂ ω3 PUFA and CVD risk factors

DepnerChristopherNutritionMetabolomicAnalysisOmega-3_SupportingInformation.zip

Background: Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease and a risk factor for cirrhosis, hepatocellular carcinoma and liver failure. Previously, we reported that dietary docosahexaenoic acid (DHA, 22:6,n-3) was more effective than eicosapentaenoic acid (EPA, 20:5,n-3) at reversing western diet (WD) induced NASH in LDLR-/- mice. Methods: Using livers from our previous study, we carried out a global non-targeted metabolomic approach to quantify diet-induced changes in hepatic metabolism. Results: Livers from WD + olive oil (WD + O)-fed mice displayed histological and gene expression features consistent with NASH. The metabolomic analysis of 320 metabolites established that the WD and n-3 polyunsaturated fatty acid (PUFA) supplementation had broad effects on all major metabolic pathways. Livers from WD + O-fed mice were enriched in saturated (SFA) and monounsaturated fatty acids (MUFA), palmitoylsphingomyelin, cholesterol, n-6 PUFA, n-6 PUFA-containing phosphoglycerolipids, n-6 PUFA-derived oxidized lipids (12-HETE) and depleted of C20-22 n-3 PUFA-containing phosphoglycerolipids, C20-22 n-3 PUFA-derived oxidized lipids (18-HEPE, 17,18-DiHETE) and S-lactoylglutathione, a methylglyoxal detoxification product. WD + DHA was more effective than WD + EPA at attenuating WD + O-induced changes in NASH gene expression markers, n-6 PUFA and oxidized lipids, citrate and S-lactosyl glutathione. Diet-induced changes in hepatic MUFA and sphingolipid content were associated with changes in expression of enzymes involved in MUFA and sphingolipid synthesis. Changes in hepatic oxidized fatty acids and S-lactoylglutathione, however, correlated with hepatic n-3 and n-6 C20-22 PUFA content. Hepatic C20-22 n-3 PUFA content was inversely associated with hepatic α-tocopherol and ascorbate content and positively associated with urinary F2- and F3-isoprostanes, revealing diet effects on whole body oxidative stress. Conclusion: DHA regulation of hepatic SFA, MUFA, PUFA, sphingomyelin, PUFA-derived oxidized lipids and Slactoylglutathione may explain the protective effects of DHA against WD-induced NASH in LDLR-/- mice

DepnerChristopherNutritionMetabolomicAnalysisOmega-3.pdf

Background: Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease and a risk factor for cirrhosis, hepatocellular carcinoma and liver failure. Previously, we reported that dietary docosahexaenoic acid (DHA, 22:6,n-3) was more effective than eicosapentaenoic acid (EPA, 20:5,n-3) at reversing western diet (WD) induced NASH in LDLR-/- mice. Methods: Using livers from our previous study, we carried out a global non-targeted metabolomic approach to quantify diet-induced changes in hepatic metabolism. Results: Livers from WD + olive oil (WD + O)-fed mice displayed histological and gene expression features consistent with NASH. The metabolomic analysis of 320 metabolites established that the WD and n-3 polyunsaturated fatty acid (PUFA) supplementation had broad effects on all major metabolic pathways. Livers from WD + O-fed mice were enriched in saturated (SFA) and monounsaturated fatty acids (MUFA), palmitoylsphingomyelin, cholesterol, n-6 PUFA, n-6 PUFA-containing phosphoglycerolipids, n-6 PUFA-derived oxidized lipids (12-HETE) and depleted of C20-22 n-3 PUFA-containing phosphoglycerolipids, C20-22 n-3 PUFA-derived oxidized lipids (18-HEPE, 17,18-DiHETE) and S-lactoylglutathione, a methylglyoxal detoxification product. WD + DHA was more effective than WD + EPA at attenuating WD + O-induced changes in NASH gene expression markers, n-6 PUFA and oxidized lipids, citrate and S-lactosyl glutathione. Diet-induced changes in hepatic MUFA and sphingolipid content were associated with changes in expression of enzymes involved in MUFA and sphingolipid synthesis. Changes in hepatic oxidized fatty acids and S-lactoylglutathione, however, correlated with hepatic n-3 and n-6 C20-22 PUFA content. Hepatic C20-22 n-3 PUFA content was inversely associated with hepatic α-tocopherol and ascorbate content and positively associated with urinary F2- and F3-isoprostanes, revealing diet effects on whole body oxidative stress. Conclusion: DHA regulation of hepatic SFA, MUFA, PUFA, sphingomyelin, PUFA-derived oxidized lipids and Slactoylglutathione may explain the protective effects of DHA against WD-induced NASH in LDLR-/- mice

Wearable Technologies for Developing Sleep and Circadian Biomarkers: A Summary of Workshop Discussions

The \u27International Biomarkers Workshop on Wearables in Sleep and Circadian Science\u27 was held at the 2018 SLEEP Meeting of the Associated Professional Sleep Societies. The workshop brought together experts in consumer sleep technologies and medical devices, sleep and circadian physiology, clinical translational research, and clinical practice. The goals of the workshop were: 1) characterize the term wearable for use in sleep and circadian science, and identify relevant sleep and circadian metrics for wearables to measure; 2) assess the current use of wearables in sleep and circadian science; 3) identify current barriers for applying wearables to sleep and circadian science; and 4) identify goals and opportunities for wearables to advance sleep and circadian science. For the purposes of biomarker development in the sleep and circadian fields, the workshop included the terms wearables , nearables , and ingestibles . Given the state of the current science and technology, the limited validation of wearable devices against gold standard measurements is the primary factor limiting large-scale use of wearable technologies for sleep and circadian research. As such, the workshop committee proposed a set of best practices for validation studies and guidelines regarding how to choose a wearable device for research and clinical use. To complement validation studies, the workshop committee recommends the development of a public data repository for wearable data. Finally, sleep and circadian scientists must actively engage in the development and use of wearable devices to maintain the rigor of scientific findings and public health messages based on wearable technology

Sleep and circadian disruption and the gut microbiome-possible links to dysregulated metabolism

Insufficient sleep and circadian misalignment are associated with adverse metabolic health outcomes. Alterations in gut microbial diversity occur with insufficient sleep and circadian misalignment, which can lead to modifications in microbial structure and function. Changes in microbially produced and modified metabolites such as short chain fatty acids and secondary bile acids may contribute to chronic inflammation, positive energy balance and endocrine changes, and represent potential mechanisms linking insufficient sleep and circadian misalignment with metabolic dysregulation. Literature primarily from the last two years is reviewed here, examining the impact of sleep and circadian rhythms and their disruption on the gut microbiome in human and non-human models, with an emphasis on the hypothesis that the altered gut microbiome may be one pathway by which insufficient sleep and circadian misalignment dysregulate metabolism