A missense variant in human perilipin 2 (PLIN2 Ser251Pro) reduces hepatic steatosis in mice.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is characterised by the accumulation of lipid droplets (LDs) within hepatocytes. Perilipin 2 (PLIN2) is the most abundant protein in hepatic LDs and its expression correlates with intracellular lipid accumulation. A recently discovered PLIN2 coding variant, Ser251Pro (rs35568725), was found to promote the accumulation of small LDs in embryonic kidney cells. In this study, we investigate the role of PLIN2-Ser251Pro (PLIN2-Pro251) on hepatic LD metabolism in vivo and research the metabolic phenotypes associated with this variant in humans. Methods: For our animal model, we used Plin2 knockout mice in which we expressed either human PLIN2-Pro251 (Pro251 mice) or wild-type human PLIN2-Ser251 (Ser251 mice) in a hepatocyte-specific manner. We fed both cohorts a lipogenic high-fat, high-cholesterol, high-fructose diet for 12 weeks. Results: Pro251 mice were associated with reduced liver triglycerides (TGs) and had lower mRNA expression of fatty acid synthase and diacylglycerol O-acyltransferase-2 compared with Ser251 mice. Moreover, Pro251 mice had a reduction of polyunsaturated fatty acids-TGs and reduced expression of epoxygenase genes. For our human study, we analysed the Penn Medicine BioBank, the Million Veteran Program, and UK Biobank. Across these databases, the minor allele frequency of PLIN2-Pro251 was approximately 5%. There was no association with the clinical diagnosis of NAFLD, however, there was a trend toward reduced liver fat in PLIN2-Pro251 carriers by MRI-spectroscopy in UK Biobank subjects. Conclusions: In mice lacking endogenous Plin2, expression of human PLIN2-Pro251 attenuated high-fat, high-fructose, high-cholesterol, diet-induced hepatic steatosis compared with human wild-type PLIN2-Ser251. Moreover, Pro251 mice had lower polyunsaturated fatty acids-TGs and epoxygenase genes expression, suggesting less liver oxidative stress. In humans, PLIN2-Pro251 is not associated with NAFLD. Impact and Implications: Lipid droplet accumulation in hepatocytes is the distinctive characteristic of non-alcoholic fatty liver disease. Perilipin 2 (PLIN2) is the most abundant protein in hepatic lipid droplets; however, little is known on the role of a specific polymorphism PLIN2-Pro251 on hepatic lipid droplet metabolism. PLIN2-Pro251 attenuates liver triglycerides accumulation after a high-fat-high-glucose-diet. PLIN2-Pro251 may be a novel lipid droplet protein target for the treatment of liver steatosis.

Ceramide synthase 6 (CerS6) is upregulated in alcohol-associated liver disease and exhibits sex-based differences in the regulation of energy homeostasis and lipid droplet accumulation.

OBJECTIVE: Alcohol-associated liver disease (ALD) is the leading cause of liver-related mortality worldwide. Current strategies to manage ALD focus largely on advanced stage disease, however, metabolic changes such as glucose intolerance are apparent at the earliest stage of alcoholic steatosis and increase the risk of disease progression. Ceramides impair insulin signaling and accumulate in ALD, and metabolic pathways involving ceramide synthase 6 (CerS6) are perturbed in ALD during hepatic steatosis. In this study, we aimed to investigate the role of CerS6 in ALD development and the relevance of CerS6 to human ALD. METHODS: C57BL/6 WT and CerS6 KO mice of both sexes were fed either a Lieber-DeCarli control (CON) or 15% ethanol (EtOH) diet for six weeks. In vivo metabolic tests including glucose and insulin tolerance tests (GTT and ITT) and energy expenditure were performed. The mice were euthanized, and serum and liver lipids and liver histology were examined. For in vitro studies, CerS6 was deleted in human hepatocytes, VL17A and cells were incubated with EtOH and/or C16:0-ceramides. RNAseq analysis was performed in livers from mice and human patients with different stages of ALD and diseased controls. RESULTS: After six weeks on an EtOH diet, CerS6 KO mice had reduced body weight, food intake, and %fat mass compared to WT mice. Energy expenditure increased in both male and female KO mice, however, was only statistically significant in male mice. In response to EtOH, WT mice developed mild hepatic steatosis, while steatosis was ameliorated in KO mice as determined by H&E and ORO staining. KO mice showed significantly decreased long-chain ceramide species, especially C16:0-ceramides, in the serum and liver tissues compared to WT mice. CerS6 deletion decreased serum TG and NEFA only in male not female mice. CerS6 deletion improved glucose tolerance and insulin resistance in EtOH-fed mice of both sexes. RNAseq analysis revealed that 74 genes are significantly upregulated and 66 genes are downregulated by CerS6 deletion in EtOH-fed male mice, with key network pathways including TG biosynthetic process, positive regulation of lipid localization, and fat cell differentiation. Similar to RNAseq results, absence of CerS6 significantly decreased mRNA expression of lipid droplet associated proteins in EtOH-fed mice. In vitro, EtOH stimulation significantly increased PLIN2 protein expression in VL17A cells while CerS6 deletion inhibited EtOH-mediated PLIN2 upregulation. C16:0-ceramide treatment significantly increased PLIN2 protein expression compared to CON. Notably, progression of ALD in humans was associated with increased hepatic CerS6 expression. CONCLUSIONS: Our findings demonstrate that CerS6 deletion improves glucose homeostasis in alcohol-fed mice and exhibits sex-based differences in the attenuation of EtOH-induced weight gain and hepatic steatosis. Additionally, we unveil that CerS6 plays a major role as a regulator of lipid droplet biogenesis in alcohol-induced intra-hepatic lipid droplet formation, identifying it as a putative target for early ALD management.

Comparison of Quality of Life and Cosmetic Outcome of Latissimus Dorsi Mini-Flap With Breast Conservation Surgery Without Reconstruction.

PURPOSE: Latissimus dorsi mini-flap (LDMF) reconstruction after breast-conserving surgery (BCS) is a useful volume replacement technique when a large tumor is located in the upper or outer portion of the breast. However, few studies have reported the impact of LDMF on patients' quality of life (QoL) and cosmesis compared with conventional BCS. METHODS: We identified patients who underwent BCS with or without LDMF between 2010 and 2020 at a single center. At least 1 year after surgery, we prospectively administered the BREAST-Q to assess QoL and obtained the patients' breast photographs. The cosmetic outcome was assessed using four panels composed of physicians and the BCCT.core software. RESULTS: A total of 120 patients were enrolled, of whom 62 and 58 underwent LDMF or BCS only, respectively. The LDMF group had significantly larger tumors, shorter nipple-to-tumor distances in preoperative examinations, and larger resected breast volumes than did the BCS-only group (p < 0.001). The questionnaires revealed that QoL was poorer in the LDMF group, particularly in terms of the physical well-being score (40.9 vs. 20.1, p < 0.001). Notably, the level of patients' cosmetic satisfaction with their breasts was comparable, and the cosmetic evaluation was assessed by panels and the BCCT.core software showed no differences between the groups. CONCLUSION: Our results showed that cosmetic outcomes of performing LDMF are comparable to those of BCS alone while having the advantage of resecting larger volumes of breast tissue. Therefore, for those who strongly wish to preserve the cosmesis of their breasts, LDMF can be considered a favorable surgical option after the patient is oriented toward the potential for physical dysfunction after surgery.

Concomitant western diet and chronic-binge alcohol dysregulate hepatic metabolism.

BACKGROUND AND AIMS: There is significant overlap between non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) with regards to risk factors and disease progression. However, the mechanism by which fatty liver disease arises from concomitant obesity and overconsumption of alcohol (syndrome of metabolic and alcohol-associated fatty liver disease; SMAFLD), is not fully understood. METHODS: Male C57BL6/J mice were fed chow diet (Chow) or high-fructose, high-fat, high-cholesterol diet (FFC) for 4 weeks, then administered either saline or ethanol (EtOH, 5% in drinking water) for another 12 weeks. The EtOH treatment also consisted of a weekly 2.5 g EtOH/kg body weight gavage. Markers for lipid regulation, oxidative stress, inflammation, and fibrosis were measured by RT-qPCR, RNA-seq, Western blot, and metabolomics. RESULTS: Combined FFC-EtOH induced more body weight gain, glucose intolerance, steatosis, and hepatomegaly compared to Chow, EtOH, or FFC. Glucose intolerance by FFC-EtOH was associated with decreased hepatic protein kinase B (AKT) protein expression and increased gluconeogenic gene expression. FFC-EtOH increased hepatic triglyceride and ceramide levels, plasma leptin levels, hepatic Perilipin 2 protein expression, and decreased lipolytic gene expression. FFC and FFC-EtOH also increased AMP-activated protein kinase (AMPK) activation. Finally, FFC-EtOH enriched the hepatic transcriptome for genes involved in immune response and lipid metabolism. CONCLUSIONS: In our model of early SMAFLD, we observed that the combination of an obesogenic diet and alcohol caused more weight gain, promoted glucose intolerance, and contributed to steatosis by dysregulating leptin/AMPK signaling. Our model demonstrates that the combination of an obesogenic diet with a chronic-binge pattern alcohol intake is worse than either insult alone.

The Impact of Phytochemicals in Obesity-Related Metabolic Diseases: Focus on Ceramide Metabolism.

The prevalence of obesity and related metabolic diseases has increased dramatically worldwide. As obesity progresses, various lipid species accumulate in ectopic tissues. Amongst them, ceramides-a deleterious sphingolipid species-accumulate and cause lipotoxicity and metabolic disturbances. Dysregulated ceramide metabolism appears to be a key feature in the pathogenesis of obesity-related metabolic diseases. Notably, dietary modification might have an impact on modulating ceramide metabolism. Phytochemicals are plant-derived compounds with various physiological properties, which have been shown to protect against obesity-related metabolic diseases. In this review, we aim to examine the impact of a myriad of phytochemicals and their dietary sources in altering ceramide deposition and ceramide-related metabolism from in vitro, in vivo, and human clinical/epidemiological studies. This review discusses how numerous phytochemicals are able to alleviate ceramide-induced metabolic defects and reduce the risk of obesity-related metabolic diseases via diverse mechanisms.

The Gangwon Obesity and Metabolic Syndrome Study: Methods and Initial Baseline Data.

Background: The prevalence of obesity has been continuously increasing, especially in rural areas of South Korea. Therefore, it is important to examine various genetic, behavioral, and environmental factors associated with obesity in these rural areas. The Korean Society for the Study of Obesity commenced a community-based prospective cohort study of the Gangwon area called the Gangwon Obesity and Metabolic Syndrome (GOMS) study to investigate longitudinal changes in the status of obesity and its related factors. Methods: A total of 317 adults 40-69 years of age were recruited from Hongcheon and Inje districts, Gangwon province, as part of the first wave of this cohort study. Information on participants' demographic, behavioral, psychological, dietary, and environmental factors and past medical histories were collected by self-administered questionnaires and interviewer-administered questionnaires. Anthropometric measurements, blood tests, and a hand grip strength test were performed, and skin keratin and stool samples were collected. Among the 317 enrolled subjects, two participants who did not have anthropometric data were excluded from the data analyses, resulting in an inclusion of a total of 315 participants. Results: The mean age of the 315 participants in the GOMS initial baseline survey was 58.5 years old, 87 of them were men, and the mean body mass index was 24.7±3.7 kg/m2. Among all participants, 48.9% had hypertension, 21.4% had diabetes mellitus (DM), 55.6% had dyslipidemia, and 46.0% had metabolic syndrome (MS). Both the prevalence rates of DM and MS were significantly higher in men. Conclusion: The first baseline survey of the GOMS study was initiated, and a more detailed analysis of respondents' data is expected to be continued. Further follow-up and additional recruitment will allow the investigation of risk factors and the etiology of obesity and its comorbidities in rural areas of Gangwon province.

Dietary vitamin B6 restriction aggravates neurodegeneration in mice fed a high-fat diet.

AIMS: It is well known that a low-status of B vitamins is associated with cognitive impairment. However, the impact of vitamin B6 (VB6) restriction on neurodegenerative diseases and its underlying mechanisms are rarely understood. This study investigated whether VB6 restriction aggravates neurodegeneration in mice fed either a low-fat (LF) control diet or a high-fat (HF) diet. MAIN METHODS: Six-week-old male C57BL/6J mice were divided into 4 groups (LF7, LF1, HF7 and HF1) and fed either an LF diet [7 mg pyridoxine (PN)/kg diet], an LF with 1 mg PN/kg diet, an HF diet or an HF with 1 mg PN/kg diet for 16 weeks. Brain cortex and hippocampus were collected and used for the determination of biochemical parameters including VB6, lipid peroxides, and neurodegeneration-related mRNA and protein levels. KEY FINDINGS: VB6 restriction reduced levels of the biologically active form of VB6, pyridoxal phosphate (PLP) in the brain. Low consumption of VB6 inactivated brain-derived neurotrophic factor signaling and cell proliferation, and induced oxidative stress, endoplasmic reticulum stress and apoptotic cell death. Significant correlation between brain lipid peroxide levels and PLP levels were observed. VB6 restriction also induced characteristic features of neurodegeneration such as amyloid-ß deposition and tau hyperphosphorylation. Similarly, high-fat diet increased parameters associated with neurodegeneration. Aggravating effects of VB6 restriction were observed in both LF control and HF groups. SIGNIFICANCE: Dietary VB6 restriction plays a key role in neurodegeneration, and VB6 restriction worsens HF-induced neuronal damage in mice. Our study emphasizes the essential role of VB6 in maintaining brain health.

Carotenoids improve the development of cerebral cortical networks in formula-fed infant macaques.

Nutrition during the first years of life has a significant impact on brain development. This study characterized differences in brain maturation from birth to 6 months of life in infant macaques fed formulas differing in content of lutein, ß-carotene, and other carotenoids using Magnetic Resonance Imaging to measure functional connectivity. We observed differences in functional connectivity based on the interaction of diet, age and brain networks. Post hoc analysis revealed significant diet-specific differences between insular-opercular and somatomotor networks at 2 months of age, dorsal attention and somatomotor at 4 months of age, and within somatomotor and between somatomotor-visual and auditory-dorsal attention networks at 6 months of age. Overall, we found a larger divergence in connectivity from the breastfeeding group in infant macaques fed formula containing no supplemental carotenoids in comparison to those fed formula supplemented with carotenoids. These findings suggest that carotenoid formula supplementation influences functional brain development.

Spatiotemporal biodistribution of α-tocopherol is impacted by the source of 13C-labeled α-tocopherol in mice following a single oral dose.

Natural (RRR-) α-tocopherol (αT) is more bioactive than synthetic (all racemic, all rac-) αT, but not enough is known about the tissue kinetics of the 2 αT sources. We examined the time-course bioaccumulation of natural versus synthetic αT in tissues of young, marginally vitamin E-deficient mice using 13C-RRR-αT or 13C-all rac-αT tracers. In experiment 1, 3-week old male wild-type mice were fed a vitamin E-deficient diet for 0, 1, 2, or 3 weeks (n = 5/time point). Tissue αT levels were analyzed by HPLC-PDA. Feeding a vitamin E-deficient diet for up to 3 weeks decreased total αT concentrations in all analyzed tissues except the brain, which maintained its αT level. In experiment 2, a 2-week αT-depletion period was followed by administration of a single oral dose of 0.5 mg of 13C-RRR-αT or 13C-all rac-αT. At 12 hr, 1, 2, and 4 days post-dose, serum and multiple tissues were collected (n = 3/time point). αT was quantified by HPLC-PDA, and 13C-αT enrichment was determined by LC-MS. Both sources of 13C-αT reached maximum serum levels at 12 hr post-dose. 13C-RRR-αT levels were significantly higher than 13C-all rac-αT in serum at 1 d post-dose, and in heart, lungs, and kidney at 2d post-dose. In brain, 13C-RRR-αT concentrations were significantly higher than 13C-all rac-αT at 2 and 4 d post-dose. At 4 d post-dose, 13C-αT levels were similar between the 2 sources in examined tissues except for brain and adipose tissue where 13C-RRR-αT was higher. In conclusion, αT bioaccumulation over time varied substantially depending on αT source and tissue type.

Experimental models of metabolic and alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a multi-systemic disease that is considered the hepatic manifestation of metabolic syndrome (MetS). Because alcohol consumption in NAFLD patients is common, there is a significant overlap in the pathogenesis of NAFLD and alcoholic liver disease (ALD). Indeed, MetS also significantly contributes to liver injury in ALD patients. This "syndrome of metabolic and alcoholic steatohepatitis" (SMASH) is thus expected to be a more prevalent presentation in liver patients, as the obesity epidemic continues. Several pre-clinical experimental models that couple alcohol consumption with NAFLD-inducing diet or genetic obesity have been developed to better understand the pathogenic mechanisms of SMASH. These models indicate that concomitant MetS and alcohol contribute to lipid dysregulation, oxidative stress, and the induction of innate immune response. There are significant limitations in the applicability of these models to human disease, such as the ability to induce advanced liver injury or replicate patterns in human food/alcohol consumption. Thus, there remains a need to develop models that accurately replicate patterns of obesogenic diet and alcohol consumption in SMASH patients.

Infant Rhesus Macaque Brain α-Tocopherol Stereoisomer Profile Is Differentially Impacted by the Source of α-Tocopherol in Infant Formula.

BACKGROUND: α-Tocopherol (αT) in its natural form [2'R, 4'R, 8'R αT (RRR-αT)] is more bioactive than synthetic α-tocopherol (all rac-αT). All rac-αT is widely used in infant formulas, but its accretion in formula-fed infant brain is unknown. OBJECTIVE: We sought to compare αT and stereoisomer status in infant rhesus macaques (Macaca mulatta) fed infant formula (RRR-αT or all rac-αT) with a reference group fed a mixed diet of breast milk and maternal diet. METHODS: From 1 d after birth until 6 mo of age, infants (n = 23) were either nursery reared and exclusively fed 1 of 2 formulas by staff personnel or were community housed with their mothers and consumed a mixed reference diet of breast milk (69 mL/d at 6 mo) transitioning to monkey diet at ∼2 mo (MF; n = 8). Formulas contained either 21 µmol RRR-αT/L (NAT-F; n = 8) or 30 µmol all rac-αT/L (SYN-F; n = 7). Total αT and αT stereoisomers were analyzed in breast milk at 2, 4, and 6 mo and in monkey plasma and liver and 6 brain regions at 6 mo of age. α-Tocopherol transfer protein (α-TTP), lipoprotein αT, and urinary α-carboxyethyl-hydroxychroman (α-CEHC) were measured. One-way ANOVA with Tukey's post-hoc test was used for analysis. RESULTS: At study termination, plasma, liver, lipoprotein, and brain total αT did not differ between groups. However, the NAT-F-fed group had higher RRR-αT than the SYN-F-fed group (P < 0.01) and the MF group (P < 0.0001) in plasma (1.7- and 2.7-fold) and brain (1.5- and 2.5-fold). Synthetic αT 2R stereoisomers (SYNTH-2R) were generally 3- and 7-fold lower in brain regions of the NAT-F group compared with those of the SYN-F and MF groups (P < 0.05). SYNTH-2R stereoisomers were 2-fold higher in MF than SYN-F (P < 0.0001). The plasma percentage of SYNTH-2R was negatively correlated with the brain percentage of RRR-αT (r = -0.99, P < 0.0001). Brain αT profiles were not explained by α-TTP mRNA or protein expression. Urine α-CEHC was 3 times higher in the NAT-F than in the MF group (P < 0.01). CONCLUSIONS: Consumption of infant formulas with natural (NAT-F) compared with synthetic (SYN-F) αT differentially impacted brain αT stereoisomer profiles in infant rhesus macaques. Future studies should assess the functional implications of αT stereoisomer profiles on brain health.

Liver-specific ceramide reduction alleviates steatosis and insulin resistance in alcohol-fed mice.

Alcohol's impairment of both hepatic lipid metabolism and insulin resistance (IR) are key drivers of alcoholic steatosis, the initial stage of alcoholic liver disease (ALD). Pharmacologic reduction of lipotoxic ceramide prevents alcoholic steatosis and glucose intolerance in mice, but potential off-target effects limit its strategic utility. Here, we employed a hepatic-specific acid ceramidase (ASAH) overexpression model to reduce hepatic ceramides in a Lieber-DeCarli model of experimental alcoholic steatosis. We examined effects of alcohol on hepatic lipid metabolism, body composition, energy homeostasis, and insulin sensitivity as measured by hyperinsulinemic-euglycemic clamp. Our results demonstrate that hepatic ceramide reduction ameliorates the effects of alcohol on hepatic lipid droplet (LD) accumulation by promoting VLDL secretion and lipophagy, the latter of which involves ceramide cross-talk between the lysosomal and LD compartments. We additionally demonstrate that hepatic ceramide reduction prevents alcohol's inhibition of hepatic insulin signaling. These effects on the liver are associated with a reduction in oxidative stress markers and are relevant to humans, as we observe peri- LD ASAH expression in human ALD. Together, our results suggest a potential role for hepatic ceramide inhibition in preventing ALD.

Alcohol effects on hepatic lipid metabolism.

Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease with significant morbidity and mortality worldwide. ALD begins with simple hepatic steatosis and progresses to alcoholic steatohepatitis, fibrosis, and cirrhosis. The severity of hepatic steatosis is highly associated with the development of later stages of ALD. This review explores the disturbances of alcohol-induced hepatic lipid metabolism through altered hepatic lipid uptake, de novo lipid synthesis, fatty acid oxidation, hepatic lipid export, and lipid droplet formation and catabolism. In addition, we review emerging data on the contributions of genetics and bioactive lipid metabolism in alcohol-induced hepatic lipid accumulation.

Rapid Lipid Droplet Isolation Protocol Using a Well-established Organelle Isolation Kit.

Lipid droplets (LDs) are bioactive organelles found within the cytosol of the most eukaryotic and some prokaryotic cells. LDs are composed of neutral lipids encased by a monolayer of phospholipids and proteins. Hepatic LD lipids, such as ceramides, and proteins are implicated in several diseases that cause hepatic steatosis. Although previous methods have been established for LD isolation, they require a time-consuming preparation of reagents and are not designed for the isolation of multiple subcellular compartments. We sought to establish a new protocol to enable the isolation of LDs, endoplasmic reticulum (ER), and lysosomes from a single mouse liver. Further, all reagents used in the protocol presented here are commercially available and require minimal reagent preparation without sacrificing LD purity. Here we present data comparing this new protocol to a standard sucrose gradient protocol, demonstrating comparable purity, morphology, and yield. Additionally, we can isolate ER and lysosomes using the same sample, providing detailed insight into the formation and intracellular flux of lipids and their associated proteins.

Early-life Programming of Type 2 Diabetes Mellitus: Understanding the Association between Epigenetics/Genetics and Environmental Factors.

Type 2 Diabetes Mellitus is an increasing public health problem that poses a severe social and economic burden affecting both developed and developing countries. Defects in insulin signaling itself are among the earliest indications that an individual is predisposed to the development of insulin resistance and subsequently Type 2 Diabetes Mellitus. To date, however, the underlying molecular mechanisms which result in resistance to the actions of insulin are poorly understood. Furthermore, it has been shown that maternal obesity is associated with an increased risk of obesity and insulin resistance in the offspring. However, the genetic and/or epigenetic modifications within insulin-sensitive tissues such as the liver and skeletal muscle, which contribute to the insulin-resistant phenotype, still remain unknown. More importantly, a lack of in-depth understanding of how the early life environment can have long-lasting effects on health and increased risk of Type 2 Diabetes Mellitus in adulthood poses a major limitation to such efforts. The focus of the current review is thus to discuss recent experimental and human evidence of an epigenetic component associated with components of nutritional programming of Type 2 Diabetes Mellitus, including altered feeding behavior, adipose tissue, and pancreatic beta-cell dysfunction, and transgenerational risk transmission.

13C-lutein is differentially distributed in tissues of an adult female rhesus macaque following a single oral administration: a pilot study.

Despite the growing awareness regarding lutein's putative roles in eyes and brain, its pharmacokinetics and tissue distribution in primates have been poorly understood. We hypothesized that 13C-lutein will be differentially distributed into tissues of an adult rhesus macaque (Macaca mulatta) 3 days following a single oral dose. After a year of prefeeding a diet supplemented with unlabeled lutein (1 µmol/kg/d), a 19-year-old female was dosed with 1.92 mg of highly enriched 13C-lutein. Tissues of a nondosed, lutein-fed monkey were used as a reference for natural abundance of 13C-lutein. On the third day postdose, plasma and multiple tissues were collected. Lutein was quantified by high-performance liquid chromatography-photodiode array detector, and 13C-lutein tissue enrichment was determined by liquid chromatography quadrupole time-of-flight mass spectrometry. In the tissues of a reference monkey, 12C-lutein with natural abundance of 13C-lutein was detectable. In the dosed monkey, highly enriched 13C-lutein was observed in all analyzed tissues except for the macular and peripheral retina, with the highest concentrations in the liver followed by the adrenal gland and plasma. 13C-lutein accumulated differentially across 6 brain regions. In adipose depots, 13C-lutein was observed, with the highest concentrations in the axillary brown adipose tissues. In summary, we evaluated 13C-lutein tissue distribution in a nonhuman primate following a single dose of isotopically labeled lutein. These results show that tissue distribution 3 days following a dose of lutein varied substantially dependent on tissue type.

Relationships of carotenoid-related gene expression and serum cholesterol and lipoprotein levels to retina and brain lutein deposition in infant rhesus macaques following 6 months of breastfeeding or formula feeding.

The purpose of this study was to investigate if the enhanced bioaccumulation of lutein in retina and brain of breastfed, compared to formula-fed, infant monkeys was associated with higher levels of serum total and HDL cholesterol, apolipoproteins, or mRNA/protein expression of carotenoid-related genes. Newborn rhesus macaques were either breastfed, fed a carotenoid-supplemented formula, or fed an unsupplemented formula for 6 months (n = 8, 8, 7). Real-time qPCR and western blotting were performed in two brain regions (occipital cortex and cerebellum) and two retina regions (macular and peripheral retina). Breastfed infants had higher serum total cholesterol, HDL cholesterol, apoA-I, and apoB-100 levels than the combined formula-fed groups (P < 0.05). Breast milk or infant formulas did not alter expression of the nine genes (CD36, SCARB1, SCARB2, LDLR, STARD3, GSTP1, BCO1, BCO2, RPE65) examined except for SCARB2 in the retina and brain regions. In conclusion, dietary regimen did not impact the expression of carotenoid-related genes except for SCARB2. However, carotenoid-related genes were differentially expressed across brain and retina regions. Breastfed infants had higher serum total and HDL cholesterol, and apolipoproteins, suggesting that lipoprotein levels might be important for delivering lutein to tissues, especially the macular retina, during infancy.

Lutein Is Differentially Deposited across Brain Regions following Formula or Breast Feeding of Infant Rhesus Macaques.

Background: Lutein, a yellow xanthophyll, selectively accumulates in primate retina and brain. Lutein may play a critical role in neural and retinal development, but few studies have investigated the impact of dietary source on its bioaccumulation in infants. Objective: We explored the bioaccumulation of lutein in infant rhesus macaques following breastfeeding or formula-feeding. Methods: From birth to 6 mo of age, male and female rhesus macaques (Macaca mulatta) were either breastfed (BF) (n = 8), fed a formula supplemented with lutein, zeaxanthin, ß-carotene, and lycopene (237, 19.0, 74.2, and 338 nmol/kg, supplemented formula-fed; SF) (n = 8), or fed a formula with low amounts of these carotenoids (38.6, 2.3, 21.5, and 0 nmol/kg, unsupplemented formula-fed; UF) (n = 7). The concentrations of carotenoids in serum and tissues were analyzed by HPLC. Results: At 6 mo of age, the BF group exhibited significantly higher lutein concentrations in serum, all brain regions, macular and peripheral retina, adipose tissue, liver, and other tissues compared to both formula-fed groups (P < 0.001). Lutein concentrations were higher in the SF group than in the UF group in serum and all tissues, with the exception of macular retina. Lutein was differentially distributed across brain areas, with the highest concentrations in the occipital cortex, regardless of the diet. Zeaxanthin was present in all brain regions but only in the BF infants; it was present in both retinal regions in all groups but was significantly enhanced in BF infants compared to either formula group (P < 0.001). ß-Carotene accumulated across brain regions in all groups, but was not detected in retina. Although lycopene was found in many tissues of the SF group, it was not detected in the brain or retina. Conclusions: Although carotenoid supplementation of infant formula significantly increased serum and tissue lutein concentrations compared to unsupplemented formula, concentrations were still well below those in BF infants. Regardless of diet, occipital cortex showed selectively higher lutein deposition than other brain regions, suggesting lutein's role in visual processing in early life.

Processed and raw tomato consumption and risk of prostate cancer: a systematic review and dose-response meta-analysis.

BACKGROUND: Prostate cancer (PCa) is the second most frequently diagnosed cancer among men worldwide. Many epidemiological studies have found an inverse association between increased tomato consumption and PCa risk. This study aims to determine the associations between consumption of various types of tomato products and PCa risk and to investigate potential dose-response relationships. METHODS: We conducted a systematic review and dose-response meta-analysis of dietary tomato in relation to PCa. Eligible studies were published before April 10, 2017 and were identified from PubMed, Web of Science, and the Cochrane Library. We estimated pooled risk ratios (RRs) and 95% confidence intervals (CI) using random and fixed effects models. Linear and nonlinear dose-response relationships were also evaluated for PCa risk. RESULTS: Thirty studies related to tomato consumption and PCa risk were included in the meta-analysis, which summarized data from 24,222 cases and 260,461 participants. Higher total tomato consumption was associated with a reduced risk of PCa (RR = 0.81, 95% CI: 0.71-0.92, p = 0.001). Specifically, tomato foods (RR = 0.84, 95% CI: 0.72-0.98, p = 0.030) and cooked tomatoes and sauces (RR = 0.84, 95% CI: 0.73-0.98, p = 0.029) were associated with a reduced risk of PCa. However, no associations were found for raw tomatoes (RR = 0.96, 95% CI: 0.84-1.09, p = 0.487). There was a significant dose-response association observed for total tomato consumption (p = 0.040), cooked tomatoes and sauces (p < 0.001), and raw tomatoes (p = 0.037), but there was not a significant association with tomato foods (plinear = 0.511, pnonlinear = 0.289). CONCLUSIONS: Our data demonstrate that increased tomato consumption is inversely associated with PCa risk. These findings were accompanied with dose-response relationships for total tomato consumption and for cooked tomatoes and sauces. Further studies are required to determine the underlying mechanisms of these associations.

Soy Consumption and the Risk of Prostate Cancer: An Updated Systematic Review and Meta-Analysis.

Prostate cancer (PCa) is the second most commonly diagnosed cancer in men, accounting for 15% of all cancers in men worldwide. Asian populations consume soy foods as part of a regular diet, which may contribute to the lower PCa incidence observed in these countries. This meta-analysis provides a comprehensive updated analysis that builds on previously published meta-analyses, demonstrating that soy foods and their isoflavones (genistein and daidzein) are associated with a lower risk of prostate carcinogenesis. Thirty articles were included for analysis of the potential impacts of soy food intake, isoflavone intake, and circulating isoflavone levels, on both primary and advanced PCa. Total soy food (p < 0.001), genistein (p = 0.008), daidzein (p = 0.018), and unfermented soy food (p < 0.001) intakes were significantly associated with a reduced risk of PCa. Fermented soy food intake, total isoflavone intake, and circulating isoflavones were not associated with PCa risk. Neither soy food intake nor circulating isoflavones were associated with advanced PCa risk, although very few studies currently exist to examine potential associations. Combined, this evidence from observational studies shows a statistically significant association between soy consumption and decreased PCa risk. Further studies are required to support soy consumption as a prophylactic dietary approach to reduce PCa carcinogenesis.