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Introduction: Physical exercise is well-recognized for its beneficial effects on health. Acute or short-term effects of exercise have been extensively studied; however, it remains unclear whether exercise in juvenile has sustained beneficial effects until old age. Hypothesis: We hypothesized that juvenile exercise would delay frailty and promote metabolic health in aged mice. Methods: Male and female mice were divided into sedentary and exercise groups, and each group contains 50 mice. Mice in exercise group started swimming at 1 month of age and stopped at 4 month of age (1.5 hour per day and 5 days per week). No exercise intervention was conducted in other time. The general health, cardiac function, metabolism and other parameters were examined in aged mice. Transcriptional profiling of various tissues and organs was performed to obtain insight into mechanisms that how juvenile exercise affects aged mice. Results: Juvenile exercise mice showed significant reduction in frailty and improvement in metabolic health compared with sedentary controls. Both male and female juvenile exercise mice were scored lower in frailty at the age of 24 months. Juvenile exercise improved the integument and physical/musculoskeletal status of male mice. For females, juvenile exercise reduced frailty in all aspects. Female juvenile exercise mice weighted more than sedentary mice at 24 months old but male groups showed no difference. The cardiac function, food consumption, grip strength and rotarod running time between two groups also presented no difference at 24 months. Juvenile exercise mice showed improved flexibility in substrate usage at the age of 24 months under fasting condition. Aged mice in exercise group showed significant higher energy expenditure, fat and carbohydrate oxidation than their controls. KEGG overrepresentation analysis for the differentially expressed genes demonstrated that pathways altered by juvenile exercise were most related to metabolism, especially lipid metabolism. Conclusions: These results demonstrate that regular and moderate physical exercise in juvenile age extends health span in mice, highlighting the sustained beneficial effects of juvenile exercise.

Hyperlipidemia is closely associated with various liver diseases, and effective intervention for prevention and treatment is in great need. Here, we aim to explore the protective effects of punicalagin (PU), a major ellagitannin in pomegranate, on acute hyperlipidemia-induced hepatic lipid metabolic disorders. Male C57bl/6J mice were pretreated with 50 or 200 mg kg−1 day−1 PU for 9 days before the injection of poloxamer 407 to induce acute hyperlipidemia. PU significantly lowered lipids and liver damage markers in serum, reduced excessive lipid accumulation in the liver, attenuated hepatic oxidative stress by activating the NF-E2 related factor 2 (Nrf2)-mediated antioxidant pathway, and enhanced hepatic mitochondrial complex activities and mitochondrial DNA copy number by promoting the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)-mediated mitochondrial biogenesis pathway. Moreover, the decreased mitochondrial fusion-related proteins were also restored by PU treatment. In vitro, PU effectively decreased triglycerides and total cholesterol levels, up-regulated Nrf2 and mitochondrial biogenesis pathways and partially restored the mitochondrial morphology in palmitic acid-treated HepG2 cells. These results suggest that PU could improve acute hyperlipidemia-induced hepatic lipid metabolic abnormalities via decreasing oxidative stress and improving mitochondrial function both in vivo and in vitro, indicating that PU might be a potential intervention for hyperlipidemia-related liver diseases.

Mitochondrial epigenetics is rising as intriguing notion for its potential involvement in aging and diseases, while the details remain largely unexplored. Here it is shown that among the 13 mitochondrial DNA (mtDNA) encoded genes, NADH‐dehydrogenase 6 (ND6) transcript is primarily decreased in obese and type 2 diabetes populations, which negatively correlates with its distinctive hypermethylation. Hepatic mtDNA sequencing in mice unveils that ND6 presents the highest methylation level, which dramatically increases under diabetic condition due to enhanced mitochondrial translocation of DNA methyltransferase 1 (DNMT1) promoted by free fatty acid through adenosine 5’‐monophosphate (AMP)‐activated protein kinase (AMPK) activation. Hepatic knockdown of ND6 or overexpression of Dnmt1 similarly impairs mitochondrial function and induces systemic insulin resistance both in vivo and in vitro. Genetic or chemical targeting hepatic DNMT1 shows significant benefits against insulin resistance associated metabolic disorders. These findings highlight the pivotal role of ND6 epigenetic network in regulating mitochondrial function and onset of insulin resistance, shedding light on potential preventive and therapeutic strategies of insulin resistance and related metabolic disorders from a perspective of mitochondrial epigenetics., Metabolic disorders emerge as one of the biggest public health challenges with distinctive feature of elevated free fatty acid, which can promote mitochondrial translocation of DNA methyltransferase 1 in liver, resulting in hypermethylation of NADHdehydrogenase 6 (ND6) on mitochondrial DNA. Such molecular change suppresses ND6 expression and induces hepatic mitochondrial dysfunction, eventually provokes systemic insulin resistance.

Hyperlipidemia is closely associated with various liver diseases, and effective intervention for prevention and treatment is in great need. Here, we aim to explore the protective effects of punicalagin (PU), a major ellagitannin in pomegranate, on acute hyperlipidemia-induced hepatic lipid metabolic disorders. Male C57bl/6J mice were pretreated with 50 or 200 mg kg-1 day-1 PU for 9 days before the injection of poloxamer 407 to induce acute hyperlipidemia. PU significantly lowered lipids and liver damage markers in serum, reduced excessive lipid accumulation in the liver, attenuated hepatic oxidative stress by activating the NF-E2 related factor 2 (Nrf2)-mediated antioxidant pathway, and enhanced hepatic mitochondrial complex activities and mitochondrial DNA copy number by promoting the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)-mediated mitochondrial biogenesis pathway. Moreover, the decreased mitochondrial fusion-related proteins were also restored by PU treatment. In vitro, PU effectively decreased triglycerides and total cholesterol levels, up-regulated Nrf2 and mitochondrial biogenesis pathways and partially restored the mitochondrial morphology in palmitic acid-treated HepG2 cells. These results suggest that PU could improve acute hyperlipidemia-induced hepatic lipid metabolic abnormalities via decreasing oxidative stress and improving mitochondrial function both in vivo and in vitro, indicating that PU might be a potential intervention for hyperlipidemia-related liver diseases.

Nutrient sensing by the mTOR complex 1 (mTORC1) requires its translocation to the lysosomal membrane. Upon amino acids removal, mTORC1 becomes cytosolic and inactive, yet its precise subcellular localization and the mechanism of inhibition remain elusive. Here, we identified Aster‐C as a negative regulator of mTORC1 signaling. Aster‐C earmarked a special rough ER subdomain where it sequestered mTOR together with the GATOR2 complex to prevent mTORC1 activation during nutrient starvation. Amino acids stimulated rapid disassociation of mTORC1 from Aster‐C concurrently with assembly of COP I vesicles which escorted mTORC1 to the lysosomal membrane. Consequently, ablation of Aster‐C led to spontaneous activation of mTORC1 and dissociation of TSC2 from lysosomes, whereas inhibition of COP I vesicle biogenesis or actin dynamics prevented mTORC1 activation. Together, these findings identified Aster‐C as a missing link between lysosomal trafficking and mTORC1 activation by revealing an unexpected role of COP I vesicles in mTORC1 signaling.

Hyperlipidemia is associated with metabolic disorders, but the detailed mechanisms and related interventions remain largely unclear. As a functional food in Asian diets, Herba houttuyniae has been reported to have beneficial effects on health. The present research was to investigate the protective effects of Herba houttuyniae aqueous extract (HAE) on hyperlipidemia-induced liver and heart impairments and its potential mechanisms. Male C57BL/6J mice were administered with 200 or 400 mg/kg/day HAE for 9 days, followed by intraperitoneal injection with 0.5 g/kg poloxamer 407 to induce acute hyperlipidemia. HAE treatment significantly attenuated excessive serum lipids and tissue damage markers, prevented hepatic lipid deposition, improved cardiac remodeling, and ameliorated hepatic and cardiac oxidative stress induced by hyperlipidemia. More importantly, NF-E2 related factor (Nrf2)-mediated antioxidant and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1&alpha, )-mediated mitochondrial biogenesis pathways as well as mitochondrial complex activities were downregulated in the hyperlipidemic mouse livers and hearts, which may be attributable to the loss of adenosine monophosphate (AMP)-activated protein kinase (AMPK) activity: all of these changes were reversed by HAE supplementation. Our findings link the AMPK/PGC-1&alpha, /Nrf2 cascade to hyperlipidemia-induced liver and heart impairments and demonstrate the protective effect of HAE as an AMPK activator in the prevention of hyperlipidemia-related diseases.

Objective Cholesterol plays a pivotal role in mitochondrial steroidogenesis, membrane structure, and respiration. Mitochondrial membranes are intrinsically low in cholesterol content and therefore must be replenished with cholesterol from other subcellular membranes. However, the molecular mechanisms underlying mitochondrial cholesterol transport remains poorly understood. The Aster-B gene encodes a cholesterol binding protein recently implicated in cholesterol trafficking from the plasma membrane to the endoplasmic reticulum (ER). In this study, we investigated the function and underlying mechanism of Aster-B in mediating mitochondrial cholesterol transport. Methods CRISPR/Cas9 gene editing was carried out to generate cell lines deficient in Aster-B expression. The effect of Aster-B deficiency on mitochondrial cholesterol transport was examined by both confocal imaging analysis and biochemical assays. Deletion mutational analysis was also carried out to identify the function of a putative mitochondrial targeting sequence (MTS) at the N-terminus of Aster-B for its role in targeting Aster-B to mitochondria and in mediating mitochondrial cholesterol trafficking. Results Ablation of Aster-B impaired cholesterol transport from the ER to mitochondria, leading to a significant decrease in mitochondrial cholesterol content. Aster-B is also required for mitochondrial transport of fatty acids derived from hydrolysis of cholesterol esters. A putative MTS at the N-terminus of Aster-B mediates the mitochondrial cholesterol uptake. Deletion of the MTS or ablation of Arf1 GTPase which is required for mitochondrial translocation of ER proteins prevented mitochondrial cholesterol transport, leading to mitochondrial dysfunction. Conclusions We identified Aster-B as a key regulator of cholesterol transport from the ER to mitochondria. Aster-B also coordinates mitochondrial cholesterol trafficking with uptake of fatty acids derived from cholesterol esters, implicating the Aster-B protein as a novel regulator of steroidogenesis., Highlights • Ablation of Aster-B impairs cholesterol transport from the ER to mitochondria. • Aster-B couples mitochondrial cholesterol transport with uptake of fatty acids derived from hydrolysis of cholesterol ester. • An MTS at the N-terminus of Aster-B is required for the mitochondrial targeting and cholesterol transport. • Ablation or inhibition of Arf1 disrupts the mitochondrial cholesterol transport and causes mitochondrial dysfunction.

Accumulating evidence has elucidated that hyperlipidemia is closely associated with an increasing prevalence of CVDs (cardiovascular diseases) because of endothelial dysfunction. In the present study, we investigated the effect and mechanism of PU (Punicalagin), a major ellagitannin in pomegranate, on endothelial dysfunction both in vivo and in vitro. In vivo, PU significantly ameliorated hyperlipidemia-induced accumulation of serum triglyceride and cholesterol as well as endothelial and mitochondrial dysfunction of thoracic aorta. Intriguingly, the FoxO1 (forkhead box O1) pathway was activated, which may account for prevention of vascular dysfunction and mitochondrial loss via upregulating mitochondrial biogenesis. In line, through in vitro cell cultures, our study demonstrated that PU not only increased the total FoxO1 protein, but also enhanced its nuclear translocation. In addition, silencing of FoxO1 remarkably abolished the ability of PU to augment the mitochondrial biogenesis, eNOS (endothelial NO synthase) expression, and oxidative stress, implying the irreplaceable role of FoxO1 in regulating endothelial function in the presence of PU. Conversely, suppression of excessive ROS (reactive oxygen species) secured the PA (palmitate)-induced decrease of FoxO1 expression, implying that there was a cross-talk between FoxO1 pathway and ROS. Concomitantly, the inflammatory response in current study was primarily mediated via p38 MAPK/NF-κB signaling pathway besides of FoxO1 pathway. Taken together, our findings suggest that PU ameliorates endothelial dysfunction by activating FoxO1 pathway, a pivotal regulating switch of mitochondrial biogenesis.

In order to eliminate the effects of flow regimes on phase concentration measurements, electrical capacitance tomography (ECT) was employed to improve the measurement accuracy. The solid particle distribution in the flow pipelines were characterized by measuring capacitance to obtain flow patterns. An improved offline iteration online reconstruction (OIOR) algorithm was proposed as the image reconstruction for the ECT system and a method of two-dimension maximum entropy threshold image segmentation was used for further image processing. Dynamic experiments were carried out for gas/solid two-phase flows. First, the flow regime was identified by the ECT, and the results were used to trace the fluctuation of the dynamic two-phase flow online. The volume concentrations were then calculated based on the reconstructed results. The experimental results indicate that the average relative error of the concentration measurements was about 1.5% over a pulverized coal volume concentration range 0.96–4.97%.

Increasing evidence demonstrates that hyperlipidemia plays a causal role in the development of cardiovascular diseases (CVDs) due to endothelial dysfunction. Houttuynia cordata aqueous extract (HAE), using as both medicine and food, whose effect and mechanism were investigated in endothelial dysfunction. In vivo, it profoundly attenuated hyperlipidemia-induced accumulation of serum metabolites, which in turn contributed to alleviating morphologic and functional damage in vascular endothelium. Moreover, the decrease expression of FoxO1/PGC-1α and mitochondrial complexes in thoracic vessels were ameliorated by HAE administration. Through in vitro cultures, consistently, the results showed that HAE predominantly activated PGC-1α for mitochondrial biogenesis via enhancing FoxO1 expression. Additionally, silencing of FoxO1 remarkably abolished the ability of HAE to augment PGC-1α expression, implying the imperative role of FoxO1 during protection. Besides, the anti-inflammation was mainly mediated via p38 MAPK pathway. Briefly, our study demonstrated that HAE ameliorated hyperlipidemia-induced endothelial injury via upregulating FoxO1/PGC-1α and suppressing p38 MAPK.