α-Ketoglutarate prevents hyperlipidemia-induced fatty liver mitochondrial dysfunction and oxidative stress by activating the AMPK-pgc-1α/Nrf2 pathway.

α-Ketoglutarate (AKG), a crucial intermediate in the tricarboxylic acid cycle, has been demonstrated to mitigate hyperlipidemia-induced dyslipidemia and endothelial damage. While hyperlipidemia stands as a major trigger for non-alcoholic fatty liver disease, the protection of AKG on hyperlipidemia-induced hepatic metabolic disorders remains underexplored. This study aims to investigate the potential protective effects and mechanisms of AKG against hepatic lipid metabolic disorders caused by acute hyperlipidemia. Our observations indicate that AKG effectively alleviates hepatic lipid accumulation, mitochondrial dysfunction, and loss of redox homeostasis in P407-induced hyperlipidemia mice, as well as in palmitate-injured HepG2 cells and primary hepatocytes. Mechanistic insights reveal that the preventive effects are mediated by activating the AMPK-PGC-1α/Nrf2 pathway. In conclusion, our findings shed light on the role and mechanism of AKG in ameliorating abnormal lipid metabolic disorders in hyperlipidemia-induced fatty liver, suggesting that AKG, an endogenous mitochondrial nutrient, holds promising potential for addressing hyperlipidemia-induced fatty liver conditions.

Ginsenoside Rh4 prevents endothelial dysfunction as a novel AMPK activator.

BACKGROUND AND PURPOSE: The AMP-activated protein kinase (AMPK) signalling pathway is a desirable target for various cardiovascular diseases (CVD), while the involvement of AMPK-mediated specific downstream pathways and effective interventions in hyperlipidaemia-induced endothelial dysfunction remain largely unknown. Herein, we aim to identify an effective AMPK activator and to explore its efficacy and mechanism against endothelial dysfunction. EXPERIMENTAL APPROACH: Molecular docking technique was adopted to screen for the potent AMPK activator among 11 most common rare ginsenosides. In vivo, poloxamer 407 (P407) was used to induce acute hyperlipidaemia in C57BL/6J mice. In vitro, palmitic acid (PA) was used to induce lipid toxicity in HAEC cells. KEY RESULTS: We discovered the strongest binding of ginsenoside Rh4 to AMPKα1 and confirmed the action of Rh4 on AMPK activation. Rh4 effectively attenuated hyperlipidaemia-related endothelial injury and oxidative stress both in vivo and in vitro and restored cell viability, mitochondrial membrane potential and mitochondrial oxygen consumption rate in HAEC cells. Mechanistically, Rh4 bound to AMPKα1 and simultaneously up-regulated AKT/eNOS-mediated NO release, promoted PGC-1α-mediated mitochondrial biogenesis and inhibited P38 MAPK/NFκB-mediated inflammatory responses in both P407-treated mice and PA-treated HAEC cells. The AMPK inhibitor Compound C treatment completely abrogated the regulation of Rh4 on the above pathways and weakened the lowering effect of Rh4 on endothelial impairment markers, suggesting that the beneficial effects of Rh4 are AMPK dependent. CONCLUSION AND IMPLICATIONS: Rh4 may serve as a novel AMPK activator to protect against hyperlipidaemia-induced endothelial dysfunction, providing new insights into the prevention and treatment of endothelial injury-associated CVD.

Recent developments, advances and strategies in heterogeneous photocatalysts for water splitting.

Photocatalytic water splitting (PWS) is an up-and-coming technology for generating sustainable fuel using light energy. Significant progress has been made in the developing of PWS innovations over recent years. In addition to various water-splitting (WS) systems, the focus has primarily been on one- and two-steps-excitation WS systems. These systems utilize singular or composite photocatalysts for WS, which is a simple, feasible, and cost-effective method for efficiently converting prevalent green energy into sustainable H2 energy on a large commercial scale. The proposed principle of charge confinement and transformation should be implemented dynamically by conjugating and stimulating the photocatalytic process while ensuring no unintentional connection at the interface. This study focuses on overall water splitting (OWS) using one/two-steps excitation and various techniques. It also discusses the current advancements in the development of new light-absorbing materials and provides perspectives and approaches for isolating photoinduced charges. This article explores multiple aspects of advancement, encompassing both chemical and physical changes, environmental factors, different photocatalyst types, and distinct parameters affecting PWS. Significant factors for achieving an efficient photocatalytic process under detrimental conditions, (e.g., strong light absorption, and synthesis of structures with a nanometer scale. Future research will focus on developing novel materials, investigating potential synthesis techniques, and improving existing high-energy raw materials. The endeavors aim is to enhance the efficiency of energy conversion, the absorption of radiation, and the coherence of physiochemical processes.

Nuclear Factor Erythroid 2 Related Factor 2 and Mitochondria Form a Mutually Regulating Circuit in the Prevention and Treatment of Metabolic Syndrome.

Significance: Metabolic syndrome (MetS) has become a major global public health problem and there is an urgent need to elucidate its pathogenesis and find more effective targets and modalities for intervention. Recent Advances: Oxidative stress and inflammation are two of the major causes of MetS-related symptoms such as insulin resistance and obesity. Nuclear factor erythroid 2 related factor 2 (Nrf2) is one of the important systems responding to oxidative stress and inflammation. As cells undergo stress, cysteines within Kelch-like ECH-associated protein 1 (Keap1) are oxidized or electrophilically modified, allowing Nrf2 to escape ubiquitination and be translocated from the cytoplasm to the nucleus, facilitating the initiation of the antioxidant transcriptional program. Meanwhile, a growing body of evidence points out a specific modulation of mitochondrial homeostasis by Nrf2. After nuclear translocation, Nrf2 activates downstream genes involved in various aspects of mitochondrial homeostasis, including mitochondrial biogenesis and dynamics, mitophagy, aerobic respiration, and energy metabolism. In turn, mitochondria reciprocally activate Nrf2 by releasing reactive oxygen species and regulating antioxidant enzymes. Critical Issues: In this review, we first summarize the interactions between Nrf2 and mitochondria in the modulation of oxidative stress and inflammation to ameliorate MetS, then propose that Nrf2 and mitochondria form a mutually regulating circuit critical to maintaining homeostasis during MetS. Future Directions: Targeting the Nrf2-mitochondrial circuit may be a promising strategy to ameliorate MetS, such as obesity, diabetes, and cardiovascular diseases.

4EBP2-regulated protein translation has a critical role in high-fat diet-induced insulin resistance in hepatocytes.

A high-fat diet (HFD) plays a critical role in hepatocyte insulin resistance. Numerous models and factors have been proposed to elucidate the mechanism of palmitic acid (PA)-induced insulin resistance. However, proteomic studies of insulin resistance by HFD stimulation are usually performed under insulin conditions, leading to an unclear understanding of how a HFD alone affects hepatocytes. Here, we mapped the phosphorylation rewiring events in PA-stimulated HepG2 cells and found PA decreased the phosphorylation level of the eukaryotic translation initiation factor 4E-binding protein 2 (4EBP2) at S65/T70. Further experiments identified 4EBP2 as a key node of insulin resistance in either HFD mice or PA-treated cells. Reduced 4EBP2 levels increased glucose uptake and insulin sensitivity, whereas the 4EBP2_S65A/T70A mutation exacerbated PA-induced insulin resistance. Additionally, the nascent proteome revealed many glycolysis-related proteins translationally regulated by 4EBP2 such as hexokinase-2, pyruvate kinase PKM, TBC1 domain family member 4, and glucose-6-phosphate 1-dehydrogenase. In summary, we report the critical role of 4EBP2 in regulating HFD-stimulated insulin resistance in hepatocytes.

Assembly of mitochondrial succinate dehydrogenase in human health and disease.

Mitochondrial succinate dehydrogenase (SDH), also known as electron transport chain (ETC) Complex II, is the only enzyme complex engaged in both oxidative phosphorylation and the tricarboxylic acid (TCA) cycle. SDH has received increasing attention due to its crucial role in regulating mitochondrial metabolism and human health. Despite having the fewest subunits among the four ETC complexes, functional SDH is formed via a sequential and well-coordinated assembly of subunits. Along with the discovery of subunit-specific assembly factors, the dynamic involvement of the SDH assembly process in a broad range of diseases has been revealed. Recently, we reported that perturbation of SDH assembly in different tissues leads to interesting and distinct pathophysiological changes in mice, indicating a need to understand the intricate SDH assembly process in human health and diseases. Thus, in this review, we summarize recent findings on SDH pathogenesis with respect to disease and a focus on SDH assembly.

α-Ketoglutarate Attenuates Hyperlipidemia-Induced Endothelial Damage by Activating the Erk-Nrf2 Signaling Pathway to Inhibit Oxidative Stress and Mitochondrial Dysfunction.

Aims: α-Ketoglutarate (AKG) is an intermediate of the tricarboxylic acid cycle and a key hub linking amino acid metabolism and glucose oxidation. Previous studies have shown that AKG improved cardiovascular diseases such as myocardial infarction and myocardial hypertrophy through antioxidant and lipid-lowering characteristics. However, its protective effect and mechanism on endothelial injury caused by hyperlipidemia have not been elucidated yet. In this study, we tested whether AKG possesses protective effects on hyperlipidemia-induced endothelial injury and studied the mechanism. Results: AKG administration both in vivo, and in vitro significantly suppressed the hyperlipidemia-induced endothelial damage, regulated ET-1 and nitric oxide levels, and reduced the inflammatory factor interleukin-6 and matrix metallopeptidase-1 by inhibiting oxidative stress and mitochondrial dysfunction. The protective effects were achieved by the mechanism of activating the Nrf2 phase II system through the ERK signaling pathway. Innovation: These results reveal the role of the AKG-ERK-Nrf2 signaling pathway in the prevention of hyperlipidemia-induced endothelial damage, and suggest that AKG, as a mitochondria-targeting nutrient, is a potential drug for the treatment of endothelial damage in hyperlipidemia. Conclusion: AKG ameliorated the hyperlipidemia-induced endothelial damage and inflammatory response by inhibiting oxidative stress and mitochondrial dysfunction. Antioxid. Redox Signal. 39, 777-793.

Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy.

Succinate dehydrogenase, which is known as mitochondrial complex II, has proven to be a fascinating machinery, attracting renewed and increased interest in its involvement in human diseases. Herein, we find that succinate dehydrogenase assembly factor 4 (SDHAF4) is downregulated in cardiac muscle in response to pathological stresses and in diseased hearts from human patients. Cardiac loss of Sdhaf4 suppresses complex II assembly and results in subunit degradation and complex II deficiency in fetal mice. These defects are exacerbated in young adults with globally impaired metabolic capacity and activation of dynamin-related protein 1, which induces excess mitochondrial fission and mitophagy, thereby causing progressive dilated cardiomyopathy and lethal heart failure in animals. Targeting mitochondria via supplementation with fumarate or inhibiting mitochondrial fission improves mitochondrial dynamics, partially restores cardiac function and prolongs the lifespan of mutant mice. Moreover, the addition of fumarate is found to dramatically improve cardiac function in myocardial infarction mice. These findings reveal a vital role for complex II assembly in the development of dilated cardiomyopathy and provide additional insights into therapeutic interventions for heart diseases.

Electronic Metal-Support Interaction Directing the Design of Fe(III)-Based Catalysts for Efficient Advanced Oxidation Processes by Dual Reaction Paths.

Persistent organic pollutants (POPs) have a huge impact on human health due to their high toxicity and non-degradability. It is still of great difficulty to develop highly efficient catalysts toward the degradation of POPs. Herein, it is reported that regulating electronic structure of quasi-single atomic ferric iron (Fe(III)) in the VO2 support through the electronic metal-support interaction (EMSI) is a versatile strategy to enhance the catalytic activity. Activated Fe(III) can react with peroxydisulfate (PDS) to produce both radicals and high-valent iron (HVFe) simultaneously for the efficient and fast degradation of POPs. Density functional theory (DFT) calculations prove that the influence of EMSI promotes the electrons on Fe(III) 3d-bond center moving close to the Fermi level, facilitating the charge transfer from Fe(III) to the adsorbate. Through the control experiments, both the radical path by PDS and the HVFe path aroused by the EMSI are confirmed in the POP degradation process. Consequently, the Fe/VO2 catalyst exhibits record-breaking catalytic activity with the k-value as high as 56.7, 43.3 µmol s-1 g-1 for p-chlorophenol and 2,4-dichlorophenol degradation, respectively.

Human identification performed with skull's sphenoid sinus based on deep learning.

Human identification plays a significant role in the investigations of disasters and criminal cases. Human identification could be achieved quickly and efficiently via 3D sphenoid sinus models by customized convolutional neural networks. In this retrospective study, a deep learning neural network was proposed to achieve human identification of 1475 noncontrast thin-slice CT scans. A total of 732 patients were retrieved and studied (82% for model training and 18% for testing). By establishing an individual recognition framework, the anonymous sphenoid sinus model was matched and cross-tested, and the performance of the framework also was evaluated on the test set using the recognition rate, ROC curve and identification speed. Finally, manual matching was performed based on the framework results in the test set. Out of a total of 732 subjects (mean age 46.45 years ± 14.92 (SD); 349 women), 600 subjects were trained, and 132 subjects were tested. The present automatic human identification has achieved Rank 1 and Rank 5 accuracy values of 93.94% and 99.24%, respectively, in the test set. In addition, all the identifications were completed within 55 s, which manifested the inference speed of the test set. We used the comparison results of the MVSS-Net to exclude sphenoid sinus models with low similarity and carried out traditional visual comparisons of the CT anatomical aspects of the sphenoid sinus of 132 individuals with an accuracy of 100%. The customized deep learning framework achieves reliable and fast human identification based on a 3D sphenoid sinus and can assist forensic radiologists in human identification accuracy.

Hepatic Suppression of Mitochondrial Complex II Assembly Drives Systemic Metabolic Benefits.

Alternate day fasting (ADF), the most popular form of caloric restriction, has shown to improve metabolic health in preclinical subjects, while intrinsic network underpinning the process remains unclear. Here, it is found that liver undergoes dramatic metabolic reprogramming during ADF, accompanied surprisingly with unique complex II dysfunction attributing to suspended complex II assembly via suppressing SDHAF4, a recently identified assembly factor. Despite moderate mitochondrial complex II dysfunction, hepatic Sdhaf4 knockout mice present intriguingly improved glucose tolerance and systemic insulin sensitivity, consistent with mice after ADF intervention. Mechanistically, it is found that hepatocytes activate arginine-nitric oxide (NO) biosynthesis axle in response to complex II and citric acid cycle dysfunction, the release of NO from liver can target muscle and adipocytes in addition to its autocrine action for enhanced insulin sensitivity. These results highlight the pivotal role of liver in ADF-associated systemic benefits, and suggest that targeting hepatic complex II assembly can be an intriguing strategy against metabolic disorders.

Chalcone-Derived Nrf2 Activator Protects Cognitive Function via Maintaining Neuronal Redox Status.

NF-E2-related factor 2 (Nrf2), the key transcription regulator of phase II enzymes, has been considered beneficial for neuronal protection. We previously designed a novel chalcone analog, 1-(2,3,4-trimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-acrylketone (Tak), that could specifically activate Nrf2 in vitro. Here, we report that Tak confers significant hippocampal neuronal protection both in vitro and in vivo. Treatment with Tak has no significant toxicity on cultured neuronal cells. Instead, Tak increases cellular ATP production by increasing mitochondrial function and decreases the levels of reactive oxygen species by activating Nrf2-mediated phase II enzyme expression. Tak pretreatment prevents glutamate-induced excitotoxic neuronal death accompanied by suppressed mitochondrial respiration, increased superoxide production, and activation of apoptosis. Further investigation indicates that the protective effect of Tak is mediated by the Akt signaling pathway. Meanwhile, Tak administration in mice can sufficiently abrogate scopolamine-induced cognitive impairment via decreasing hippocampal oxidative stress. In addition, consistent benefits are also observed in an energy stress mouse model under a high-fat diet, as the administration of Tak remarkably increases Akt signaling-mediated antioxidative enzyme expression and prevents hippocampal neuronal apoptosis without significant effect on the mouse metabolic status. Overall, our study demonstrates that Tak protects cognitive function by Akt-mediated Nrf2 activation to maintain redox status both vivo and in vitro, suggesting that Tak is a promising pharmacological candidate for the treatment of oxidative neuronal diseases.

Hypermethylation of Hepatic Mitochondrial ND6 Provokes Systemic Insulin Resistance.

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.

Tailoring the Electronic Metal-Support Interactions in Supported Atomically Dispersed Gold Catalysts for Efficient Fenton-like Reaction.

The atomically dispersed metal is expected as one of the most promising Fenton-like catalysts for the degradation of recalcitrant organic pollutants (ROPs) by the strong "electronic metal-support interactions" (EMSIs). Here, we develop an atomically dispersed metal-atom alloy made by guest Au atoms substitute host V atoms in the two-dimensional VO2 (B) nanobelt support (Au/VO2 ) to activate Fenton-like oxidation for elimination of ROPs. The 2D nanobelt structure enlarges the exposure of atomically Au thus increasing the number of active sites to absorb more S2 O8 2- ions. And the EMSIs regulate the charge density in Au atoms to present positive charge Au+ , lowering the energy barrier of S2 O8 2- decomposition to produce SO4 .- . The Au/VO2 catalyst possesses excellent durable and reliable characteristics and exhibits record-breaking efficiency with TOF as high as 21.42 min-1 , 16.19 min-1 , and 80.89 min-1 for rhodamine, phenol, and bisphenol A degradation, respectively.

Htd2 deficiency-associated suppression of α-lipoic acid production provokes mitochondrial dysfunction and insulin resistance in adipocytes.

Mitochondria harbor a unique fatty acid synthesis pathway (mtFAS) with mysterious functions gaining increasing interest, while its involvement in metabolic regulation is essentially unknown. Here we show that 3-Hydroxyacyl-ACP dehydratase (HTD2), a key enzyme in mtFAS pathway was primarily downregulated in adipocytes of mice under metabolic disorders, accompanied by decreased de novo production of lipoic acid, which is the byproduct of mtFAS pathway. Knockdown of Htd2 in 3T3-L1 preadipocytes or differentiated 3T3-L1 mature adipocytes impaired mitochondrial function via suppression of complex I activity, resulting in enhanced oxidative stress and impaired insulin sensitivity, which were all attenuated by supplement of lipoic acid. Moreover, lipidomic study revealed limited lipid alterations in mtFAS deficient cells which primarily presenting accumulation of triglycerides, attributed to mitochondrial dysfunction. Collectively, the present study highlighted the pivotal role of mtFAS pathway in regulating mitochondrial function and adipocytes insulin sensitivity, demonstrating supportive evidence for lipoic acid being potential effective nutrient for improving insulin resistance and related metabolic disorders.

Punicalagin improves hepatic lipid metabolism via modulation of oxidative stress and mitochondrial biogenesis in hyperlipidemic mice.

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.

Punicalagin Activates AMPK/PGC-1α/Nrf2 Cascade in Mice: The Potential Protective Effect against Prenatal Stress.

SCOPE: Prenatal stress is closely associated with poor health outcomes for offspring, yet the specific mechanisms and effective interventions remain limited. METHODS AND RESULTS: In the present study, both male and female rat offspring exposed to prenatal restraint stress (PRS) are confirmed to have impaired spatial learning and memory, accompanied by reduced AMP-activated protein kinase (AMPK) activity and decreased protein expression of mitochondrial biogenesis and antioxidant pathways in the hippocampus. Interestingly, a deficiency in the AMPK cascade also occurs in liver, heart, and adipose tissues, suggesting that the systemic deactivation of AMPK in the offspring is potentially attributed to increased maternal glucocorticoid levels under PRS. Punicalagin (PU), a major ellagitannin in pomegranate, is found to effectively induce mitochondrial biogenesis and phase II enzymes through activation of AMPK in both HT22 and primary hippocampal neurons, thereby inhibiting glutamate-induced cell viability and mitochondrial membrane potential loss. Meanwhile, the activation of AMPK cascade is also confirmed in mice administrated with PU for three days. CONCLUSIONS: Altogether, these results indicate that the systemic deficiency of the AMPK cascade can be the key factor that contributes to poor outcomes of PRS, and PU may be used as an effective maternal nutritional intervention.

Heterostructured NiS2/ZnIn2S4 Realizing Toroid-like Li2O2 Deposition in Lithium-Oxygen Batteries with Low-Donor-Number Solvents.

The aprotic lithium-oxygen (Li-O2) battery has triggered tremendous efforts for advanced energy storage due to the high energy density. However, realizing toroid-like Li2O2 deposition in low-donor-number (DN) solvents is still the intractable obstruction. Herein, a heterostructured NiS2/ZnIn2S4 is elaborately developed and investigated as a promising catalyst to regulate the Li2O2 deposition in low-DN solvents. The as-developed NiS2/ZnIn2S4 promotes interfacial electron transfer, regulates the adsorption energy of the reaction intermediates, and accelerates O-O bond cleavage, which are convincingly evidenced experimentally and theoretically. As a result, the toroid-like Li2O2 product is achieved in a Li-O2 battery with low-DN solvents via the solvation-mediated pathway, which demonstrates superb cyclability over 490 cycles and a high output capacity of 3682 mA h g-1. The interface engineering of heterostructure catalysts offers more possibilities for the realization of toroid-like Li2O2 in low-DN solvents, holding great promise in achieving practical applications of Li-O2 batteries as well as enlightening the material design in catalytic systems.

Herba Houttuyniae Extract Benefits Hyperlipidemic Mice via Activation of the AMPK/PGC-1α/Nrf2 Cascade.

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-1α)-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-1α/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.