bims-kimdis 2024-07-21 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–07–21
fiveteen papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation.
Very Low Calorie Ketogenic Diet: What Effects on Lipid Metabolism?
Intermittent fasting, calorie restriction, and a ketogenic diet improve mitochondrial function by reducing lipopolysaccharide signaling in monocytes during obesity: A randomized clinical trial.
Mitochondrial bioenergetics are not associated with myofibrillar protein synthesis rates.
Intermittent Fasting Improves Social Interaction and Decreases Inflammatory Markers in Cortex and Hippocampus.
A single bout of resistance exercise triggers mitophagy, potentially involving the ejection of mitochondria in human skeletal muscle.
Differential Mitochondrial Adaptation of the Slow and Fast Skeletal Muscles by Endurance Running Exercise in Streptozotocin-Induced Diabetic Mice.
Impact of very low carbohydrate ketogenic diets on cardiovascular risk factors among patients with type 2 diabetes; GRADE-assessed systematic review and meta-analysis of clinical trials.
Aerobic exercise alleviates skeletal muscle aging in male rats by inhibiting apoptosis via regulation of the Trx system.
Intermittent Fasting in Youth: A Scoping Review.
Editorial: Recent advances in the treatment of epilepsy.
β-Hydroxybutyrate and melatonin suppress maladaptive UPR, excessive autophagy and pyroptosis in Aβ 1-42 and LPS-Induced SH-SY5Y cells.
Fatty acid synthesis promotes inflammasome activation through NLRP3 palmitoylation.
Decreased skeletal muscle intramyocellular lipid droplet-mitochondrial contact contributes to myosteatosis in cancer cachexia.
Star Power: Does fusion have a future after all?

bioRxiv. 2024 Jul 11. pii: 2024.07.09.602593. [Epub ahead of print]

Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation.

Eric D Queathem, Zahra Moazzami, David B Stagg, Alisa B Nelson, Kyle Fulghum, Abdirahman Hayir, Alisha Seay, Jacob R Gillingham, D Andre d'Avignon, Xianlin Han, Hai-Bin Ruan, Peter A Crawford, Patrycja Puchalska.

Therapeutic interventions targeting hepatic lipid metabolism in metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) remain elusive. Using mass spectrometry-based stable isotope tracing and shotgun lipidomics, we established a novel link between ketogenesis and MASLD pathophysiology. Our findings show that mouse liver and primary hepatocytes consume ketone bodies to support fatty acid (FA) biosynthesis via both de novo lipogenesis (DNL) and FA elongation. Analysis of 13 C-labeled FAs in hepatocytes lacking mitochondrial D-β-hydroxybutyrate dehydrogenase (BDH1) revealed a partial reliance on mitochondrial conversion of D-βOHB to acetoacetate (AcAc) for cytoplasmic DNL contribution, whereas FA elongation from ketone bodies was fully dependent on cytosolic acetoacetyl-CoA synthetase (AACS). Ketone bodies were essential for polyunsaturated FA (PUFA) homeostasis in hepatocytes, as loss of AACS diminished both free and esterified PUFAs. Ketogenic insufficiency depleted liver PUFAs and increased triacylglycerols, mimicking human MASLD, suggesting that ketogenesis supports PUFA homeostasis, and may mitigate MASLD-MASH progression in humans.

DOI: https://doi.org/10.1101/2024.07.09.602593
Curr Nutr Rep. 2024 Jul 15.

Very Low Calorie Ketogenic Diet: What Effects on Lipid Metabolism?

Rosario Suarez, Sebastián Chapela, Natalia Daniela Llobera, Martha Montalván, Celina Andrade Vásquez, Andres Luciano Nicolas Martinuzzi, Christos S Katsanos, Ludovica Verde, Evelyn Frias-Toral, Luigi Barrea, Giovanna Muscogiuri.

   PURPOSE OF REVIEW: This review aims to critically examine how VLCKD affects plasma lipoprotein, lipid and cholesterol metabolism. Cardiovascular disease is a worldwide health problem affecting millions of people and leading to high rates of mortality and morbidity. There is a well-established association between cardiovascular disease and circulating cholesterol. Various dietary recommendations are currently available for the management of dyslipidemia.
RECENT FINDINGS: The very low-calorie ketogenic diet (VLCKD) is becoming increasingly popular as a treatment option for several pathological conditions, including dyslipidemia. In addition to being low in calories, the VLCKD's main feature is its unique calorie distribution, emphasizing a reduction in carbohydrate consumption in favor of fat as the primary calorie source. Lowering calorie intake through a VLCKD can reduce the endogenous production of cholesterol. However, if the foods consumed are from animal sources, dietary cholesterol intake may increase due to the higher fat content of animal products. When combined, these dietary practices may have opposing effects on plasma cholesterol levels. Studies investigating the impact of VLCKD on plasma cholesterol and low-density lipoprotein cholesterol levels report contradictory findings. While some studies found an increase in low-density lipoprotein cholesterol levels, others showed a decrease in total cholesterol and low-density lipoprotein cholesterol, along with an increase in high-density lipoprotein cholesterol.

Keywords:  Cholesterol; Dyslipidemia; Hypercholesterolemia; Lipid Metabolism; Low-density lipoprotein; Obesity; Very-low-calorie ketogenic diet

DOI:  https://doi.org/10.1007/s13668-024-00556-6
Clin Nutr. 2024 Jul 05. pii: S0261-5614(24)00228-0. [Epub ahead of print]43(8): 1914-1928

Intermittent fasting, calorie restriction, and a ketogenic diet improve mitochondrial function by reducing lipopolysaccharide signaling in monocytes during obesity: A randomized clinical trial.

Martha Guevara-Cruz, Karla G Hernández-Gómez, Citlally Condado-Huerta, Luis E González-Salazar, Ana Karen Peña-Flores, Edgar Pichardo-Ontiveros, Aurora E Serralde-Zúñiga, Mónica Sánchez-Tapia, Otoniel Maya, Isabel Medina-Vera, Lilia G Noriega, Adriana López-Barradas, Oscar Rodríguez-Lima, Irma Mata, Viridiana Olin-Sandoval, Nimbe Torres, Armando R Tovar, Laura A Velázquez-Villegas.

   BACKGROUND: Mitochondrial dysfunction occurs in monocytes during obesity and contributes to a low-grade inflammatory state; therefore, maintaining good mitochondrial conditions is a key aspect of maintaining health. Dietary interventions are primary strategies for treating obesity, but little is known about their impact on monocyte bioenergetics. Thus, the aim of this study was to evaluate the effects of calorie restriction (CR), intermittent fasting (IF), a ketogenic diet (KD), and an ad libitum habitual diet (AL) on mitochondrial function in monocytes and its modulation by the gut microbiota.
METHODS AND FINDINGS: A randomized controlled clinical trial was conducted in which individuals with obesity were assigned to one of the 4 groups for 1 month. Subsequently, the subjects received rifaximin and continued with the assigned diet for another month. The oxygen consumption rate (OCR) was evaluated in isolated monocytes, as was the gut microbiota composition in feces and anthropometric and biochemical parameters. Forty-four subjects completed the study, and those who underwent CR, IF and KD interventions had an increase in the maximal respiration OCR (p = 0.025, n2p = 0.159 [0.05, 0.27] 95% confidence interval) in monocytes compared to that in the AL group. The improvement in mitochondrial function was associated with a decrease in monocyte dependence on glycolysis after the IF and KD interventions. Together, diet and rifaximin increased the gut microbiota diversity in the IF and KD groups (p = 0.0001), enriched the abundance of Phascolarctobacterium faecium (p = 0.019) in the CR group and Ruminococcus bromii (p = 0.020) in the CR and KD groups, and reduced the abundance of lipopolysaccharide (LPS)-producing bacteria after CR, IF and KD interventions compared to the AL group at the end of the study according to ANCOVA with covariate adjustment. Spearman's correlation between the variables measured highlighted LPS as a potential modulator of the observed effects. In line with this findings, serum LPS and intracellular signaling in monocytes decreased with the three interventions (CR, p = 0.002; IF, p = 0.001; and KD, p = 0.001) compared to those in the AL group at the end of the study.
CONCLUSIONS: We conclude that these dietary interventions positively regulate mitochondrial bioenergetic health and improve the metabolic profile of monocytes in individuals with obesity via modulation of the gut microbiota. Moreover, the evaluation of mitochondrial function in monocytes could be used as an indicator of metabolic and inflammatory status, with potential applications in future clinical trials.
TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (NCT05200468).

Keywords:  Dietary interventions; Gut microbiota; Mitochondrial function; Monocyte bioenergetics; Obesity

DOI:  https://doi.org/10.1016/j.clnu.2024.06.036
J Cachexia Sarcopenia Muscle. 2024 Jul 15.

Mitochondrial bioenergetics are not associated with myofibrillar protein synthesis rates.

Andrew M Holwerda, Marlou L Dirks, Pierre-Andre Barbeau, Joy Goessens, Annemie Gijsen, Luc J C van Loon, Graham P Holloway.

   BACKGROUND: Mitochondria represent key organelles influencing cellular homeostasis and have been implicated in the signalling events regulating protein synthesis.
METHODS: We examined whether mitochondrial bioenergetics (oxidative phosphorylation and reactive oxygen species (H2O2) emission, ROS) measured in vitro in permeabilized muscle fibres represent regulatory factors for integrated daily muscle protein synthesis rates and skeletal muscle mass changes across the spectrum of physical activity, including free-living and bed-rest conditions: n = 19 healthy, young men (26 ± 4 years, 23.4 ± 3.3 kg/m2) and following 12 weeks of resistance-type exercise training: n = 10 healthy older men (70 ± 3 years, 25.2 ± 2.1 kg/m2). Additionally, we evaluated the direct relationship between attenuated mitochondrial ROS emission and integrated daily myofibrillar and sarcoplasmic protein synthesis rates in genetically modified mice (mitochondrial-targeted catalase, MCAT).
RESULTS: Neither oxidative phosphorylation nor H2O2 emission were associated with muscle protein synthesis rates in healthy young men under free-living conditions or following 1 week of bed rest (both P > 0.05). Greater increases in GSSG concentration were associated with greater skeletal muscle mass loss following bed rest (r = -0.49, P < 0.05). In older men, only submaximal mitochondrial oxidative phosphorylation (corrected for mitochondrial content) was positively associated with myofibrillar protein synthesis rates during exercise training (r = 0.72, P < 0.05). However, changes in oxidative phosphorylation and H2O2 emission were not associated with changes in skeletal muscle mass following training (both P > 0.05). Additionally, MCAT mice displayed no differences in myofibrillar (2.62 ± 0.22 vs. 2.75 ± 0.15%/day) and sarcoplasmic (3.68 ± 0.35 vs. 3.54 ± 0.35%/day) protein synthesis rates when compared with wild-type mice (both P > 0.05).
CONCLUSIONS: Mitochondrial oxidative phosphorylation and reactive oxygen emission do not seem to represent key factors regulating muscle protein synthesis or muscle mass regulation across the spectrum of physical activity.

Keywords:  Aging; Muscle protein synthesis; Physical inactivity; Reactive oxygen species; Skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.13532
Mol Neurobiol. 2024 Jul 13.

Intermittent Fasting Improves Social Interaction and Decreases Inflammatory Markers in Cortex and Hippocampus.

Martín García-Juárez, Adamary García-Rodríguez, Gabriela Cruz-Carrillo, Orlando Flores-Maldonado, Miguel Becerril-Garcia, Lourdes Garza-Ocañas, Ivan Torre-Villalvazo, Alberto Camacho-Morales.

  Autism spectrum disorder (ASD) is a psychiatric condition characterized by reduced social interaction, anxiety, and stereotypic behaviors related to neuroinflammation and microglia activation. We demonstrated that maternal exposure to Western diet (cafeteria diet or CAF) induced microglia activation, systemic proinflammatory profile, and ASD-like behavior in the offspring. Here, we aimed to identify the effect of alternate day fasting (ADF) as a non-pharmacologic strategy to modulate neuroinflammation and ASD-like behavior in the offspring prenatally exposed to CAF diet. We found that ADF increased plasma beta-hydroxybutyrate (BHB) levels in the offspring exposed to control and CAF diets but not in the cortex (Cx) and hippocampus (Hpp). We observed that ADF increased the CD45 + cells in Cx of both groups; In control individuals, ADF promoted accumulation of CD206 + microglia cells in choroid plexus (CP) and increased in CD45 + macrophages cells and lymphocytes in the Cx. Gestational exposure to CAF diet promoted defective sociability in the offspring; ADF improved social interaction and increased microglia CD206 + in the Hpp and microglia complexity in the dentate gyrus. Additionally, ADF led to attenuation of the ER stress markers (Bip/ATF6/p-JNK) in the Cx and Hpp. Finally, biological modeling showed that fasting promotes higher microglia complexity in Cx, which is related to improvement in social interaction, whereas in dentate gyrus sociability is correlated with less microglia complexity. These data suggest a contribution of intermittent fasting as a physiological stimulus capable of modulating microglia phenotype and complexity in the brain, and social interaction in male mice.

Keywords:  Inflammation; Intermittent fasting; Ketone bodies; Microglia; Sociability

DOI:  https://doi.org/10.1007/s12035-024-04340-z
Acta Physiol (Oxf). 2024 Jul 18. e14203

A single bout of resistance exercise triggers mitophagy, potentially involving the ejection of mitochondria in human skeletal muscle.

Francisco Díaz-Castro, Mauro Tuñón-Suárez, Patricia Rivera, Javier Botella, Jorge Cancino, Ana María Figueroa, Juan Gutiérrez, Claudette Cantin, Louise Deldicque, Hermann Zbinden-Foncea, Joachim Nielsen, Carlos Henríquez-Olguín, Eugenia Morselli, Mauricio Castro-Sepúlveda.

   AIM: The present study aimed to investigate the effects of a single bout of resistance exercise on mitophagy in human skeletal muscle (SkM).
METHODS: Eight healthy men were recruited to complete an acute bout of one-leg resistance exercise. SkM biopsies were obtained one hour after exercise in the resting leg (Rest-leg) and the contracting leg (Ex-leg). Mitophagy was assessed using protein-related abundance, transmission electron microscopy (TEM), and fluorescence microscopy.
RESULTS: Our results show that acute resistance exercise increased pro-fission protein phosphorylation (DRP1Ser616) and decreased mitophagy markers such as PARKIN and BNIP3L/NIX protein abundance in the Ex-leg. Additionally, mitochondrial complex IV decreased in the Ex-leg when compared to the Rest-leg. In the Ex-leg, TEM and immunofluorescence images showed mitochondrial cristae abnormalities, a mitochondrial fission phenotype, and increased mitophagosome-like structures in both subsarcolemmal and intermyofibrillar mitochondria. We also observed increased mitophagosome-like structures on the subsarcolemmal cleft and mitochondria in the extracellular space of SkM in the Ex-leg. We stimulated human primary myotubes with CCCP, which mimics mitophagy induction in the Ex-leg, and found that BNIP3L/NIX protein abundance decreased independently of lysosomal degradation. Finally, in another human cohort, we found a negative association between BNIP3L/NIX protein abundance with both mitophagosome-like structures and mitochondrial cristae density in the SkM.
CONCLUSION: The findings suggest that a single bout of resistance exercise can initiate mitophagy, potentially involving mitochondrial ejection, in human skeletal muscle. BNIP3L/NIX is proposed as a sensitive marker for assessing mitophagy flux in SkM.

Keywords:  BNIP3L/NIX; mitochondria cristae; mitochondria dynamics; mitophagy

DOI:  https://doi.org/10.1111/apha.14203
Physiol Res. 2024 Jul 17. 73(3): 369-379

Differential Mitochondrial Adaptation of the Slow and Fast Skeletal Muscles by Endurance Running Exercise in Streptozotocin-Induced Diabetic Mice.

A Takemura, Y Matsunaga, T Shinya, H Matta.

The skeletal muscle is the main organ responsible for insulin action, and glucose disposal and metabolism. Endurance and/or resistance training raises the number of mitochondria in diabetic muscles. The details of these adaptations, including mitochondrial adaptations of the slow and fast muscles in diabetes, are unclear. This study aimed to determine whether exercise training in streptozotocin (STZ)-induced mice leads to differential adaptations in the slow and fast muscles, and improving glucose clearance. Eight-week-old mice were randomly distributed into normal control (CON), diabetes (DM), and diabetes and exercise (DM+Ex) groups. In the DM and DM+Ex groups, mice received a freshly prepared STZ (100 mg/kg) intraperitoneal injection on two consecutive days. Two weeks after the injection, the mice in the groups ran on a treadmill for 60 min at 20 m/min for a week and subsequently at 25 m/min for 5 weeks (5 days/week). The analyses indicated that running training at low speed (25 m/min) enhanced mitochondrial enzyme activity and expression of lactate and glucose transporters in the plantaris (low-oxidative) muscle that improved whole-body glucose metabolism in STZ-induced diabetic mice. There were no differences in glucose transporter expression levels in the soleus (high-oxidative) muscle. The endurance running exercise at 20-25 m/min was sufficient to induce mitochondrial adaptation in the low-oxidative muscles, but not in the high-oxidative muscles, of diabetic mice. In conclusion, the present study indicated that running training at 25 m/min improved glucose metabolism by increasing the mitochondrial enzyme activity and glucose transporter 4 and monocarboxylate transporter 4 protein contents in the low-oxidative muscles in STZ-induced diabetic mice.
Nutr Metab (Lond). 2024 Jul 19. 21(1): 50

Impact of very low carbohydrate ketogenic diets on cardiovascular risk factors among patients with type 2 diabetes; GRADE-assessed systematic review and meta-analysis of clinical trials.

Parisa Ghasemi, Malihe Jafari, Saber Jafari Maskouni, Seyed Ahmad Hosseini, Roksaneh Amiri, Jalal Hejazi, Mahla Chambari, Ronia Tavasolian, Mehran Rahimlou.

   OBJECTIVE: This study was designed to evaluate the impact of VLCKD on cardiovascular risk factors in patients with T2DM.
METHODS: Until March 2024, extensive searches were conducted on PubMed, Scopus, Web of Science, Embase, and other relevant databases. The purpose was to identify clinical trials examining the impact of VLCKD on glycemic control, lipid profile, and blood pressure. The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) method was used to assess the evidence's degree of certainty.
RESULTS: Our initial search found a total of 2568 records and finally 29 trials were included in final analysis. Our results showed that adherence from VLCKD led to significant reduction in fasting blood sugar (WMD= -11.68 mg/dl; 95% CI: -18.79, -4.56; P = 0.001), HbA1c (WMD= -0.29; 95% CI: -0.44, -0.14; P < 0.001), HOMA-IR(WMD= -0.71; 95% CI: -1.14, -0.29; P = 0.001), insulin (WMD= -1.45; 95% CI: -2.54, -0.36; P = 0.009), triglyceride (WMD= -17.95; 95% CI: -26.82, -9.07; P < 0.001), systolic blood pressure (WMD= -2.85, 95% CI: -4.99, -0.71; P = 0.009) and diastolic blood pressure (WMD= -1.40; 95% CI: -2.66, -0.13; P = 0.03). We also found a significant increase in high-density lipoprotein (HDL) level after adherence from VLCKD diet (WMD = 3.93, 95% CI: 2.03, 5.84; P = 0.000). We couldn't find any significant differences between groups in term of LDL and total cholesterol levels.
CONCLUSION: People following a VLCKD experience a more significant improvement in cardiovascular risk factors when compared to individuals on control diets.

Keywords:  T2DM, Meta-analysis; Type 2 diabetes; Very low carbohydrate ketogenic diets

DOI:  https://doi.org/10.1186/s12986-024-00824-w
Exp Gerontol. 2024 Jul 18. pii: S0531-5565(24)00165-7. [Epub ahead of print]194 112523

Aerobic exercise alleviates skeletal muscle aging in male rats by inhibiting apoptosis via regulation of the Trx system.

Fenmiao Bao, Xiaoqin Zhao, Jiaqi You, Yiyao Liu, Zheng Xu, Yuqing Wu, Yufeng Wu, Zujie Xu, Liang Yu, Junping Li, Yan Wei.

  Skeletal muscle aging in rats is a reduction in skeletal muscle mass caused by a decrease in the number or volume of skeletal muscle myofibers. Apoptosis has been recognized to play a key role in accelerating the process of skeletal muscle aging in rats. The thioredoxin (Trx) system is a widely expressed oxidoreductase system that controls the cellular reduction/oxidation state and has both potent anti-free radical damage and important pro-growth and apoptosis inhibitory functions. Previous studies have shown that exercise delays skeletal muscle aging. However, it is unclear whether exercise attenuates skeletal muscle aging via the Trx system. Therefore, the present study used the Trx system as an entry point to explore the effect of aerobic exercise to improve skeletal muscle aging in rats and its possible mechanisms, and to provide a theoretical basis for exercise to delay skeletal muscle aging in rats. It was shown that aerobic exercise in senescent rats resulted in increased gastrocnemius index, decreased body weight, increased endurance, decreased skeletal muscle cell apoptosis, increased activity and protein expression of the Trx system, and decreased expression of p38 and ASK1. Based on these findings, we conclude that 10 weeks of aerobic exercise may enhance the anti-apoptotic effect of Trx by up-regulating Trx and Trx reductase (TR) protein expression, which in turn increases Trx activity in rat skeletal muscle, and ultimately alleviates apoptosis in senescent skeletal muscle cells.

Keywords:  Aerobic exercise; Apoptosis; Sarcopenia; Skeletal muscle; TR; Trx

DOI:  https://doi.org/10.1016/j.exger.2024.112523
Res Sq. 2024 Jul 01. pii: rs.3.rs-4524102. [Epub ahead of print]

Intermittent Fasting in Youth: A Scoping Review.

Jomanah A Bakhsh, Alaina P Vidmar, Sarah-Jeanne Salvy.

Intermittent fasting (IF) focuses on the timing of eating rather than diet quality or energy intake, with evidence supporting its effects on weight loss and cardiometabolic outcomes in adults. However, there is limited evidence for its efficacy in adolescents and emerging adults. To address this, a scoping review examined IF regimens in individuals aged 10 to 25, focusing on methodology, intervention parameters, outcomes, adherence, feasibility, and efficacy. The review included 39 studies with 731 participants aged 15 to 25. Methodologies varied, with 18 studies on time-restricted eating and others requiring caloric restriction. Primary outcomes included cardiometabolic risk factors (11/29), body composition (9/29), anthropometric measurements (8/29), and feasibility (2/29). Most studies reported significant weight loss. This review underscores IF's potential in treating obesity in this age group but highlights the need for rigorous studies with standardized frameworks for feasibility to ensure comparability and determine IF's practicality in this age group.

DOI: https://doi.org/10.21203/rs.3.rs-4524102/v1
Front Pharmacol. 2024 ;15 1444138

Editorial: Recent advances in the treatment of epilepsy.

Khojasteh Malekmohammad, Antonella Riva, Mahmoud Rafieian-Kopaei.



Keywords:  anti-seizure medications; drug-resistance; epilepsy; ketogenic diet; neuroprotection; seizure

DOI:  https://doi.org/10.3389/fphar.2024.1444138
Mol Biol Rep. 2024 Jul 13. 51(1): 802

β-Hydroxybutyrate and melatonin suppress maladaptive UPR, excessive autophagy and pyroptosis in Aβ 1-42 and LPS-Induced SH-SY5Y cells.

Mohammad Hasan Maleki, Fatemeh Omidi, Zeinab Javanshir, Mahla Bagheri, Zobeideh Tanhadoroodzani, Sahar Dastghaib, Mesbah Shams, Mohammadarian Akbari, Sanaz Dastghaib.

   BACKGROUND: Alzheimer's disease is a neurological disease characterized by the build-up of amyloid beta peptide (Aβ) and lipopolysaccharide (LPS), which causes synapse dysfunction, cell death, and neuro-inflammation. A maladaptive unfolded protein response (UPR), excessive autophagy, and pyroptosis aggravate the disease. Melatonin (MEL) and hydroxybutyrate (BHB) have both shown promise in terms of decreasing Aβ pathology. The goal of this study was to see how BHB and MEL affected the UPR, autophagy, and pyroptosis pathways in Aβ1-42 and LPS-induced SH-SY5Y cells.
MATERIALS AND METHODS: Human neuroblastoma SH-SY5Y cells were treated with BHB, MEL, or a combination of the two after being exposed to A β1-42 and LPS. Cell viability was determined using the MTT test, and gene expression levels of UPR (ATF6, PERK, and CHOP), autophagy (Beclin-1, LC3II, P62, and Atg5), and pyroptosis-related markers (NLRP3, TXNIP, IL-1β, and NFκB1) were determined using quantitative Real-Time PCR (qRT-PCR). For statistical analysis, one-way ANOVA was employed, followed by Tukey's post hoc test.
RESULTS: BHB and MEL significantly increased SH-SY5Y cell viability in the presence of A β1-42 and LPS. Both compounds inhibited the expression of maladaptive UPR and autophagy-related genes, as well as inflammatory and pyroptotic markers caused by Aβ1-42 and LPS-induced SH-SY5Y cells.
CONCLUSION: BHB and MEL rescue neurons in A β1-42 and LPS-induced SH-SY5Y cells by reducing maladaptive UPR, excessive autophagy, and pyroptosis. More research is needed to fully comprehend the processes behind their beneficial effects and to discover their practical applications in the treatment of neurodegenerative disorders.

Keywords:  Alzheimer; Autophagy; Ketone metabolism; Melatonin; UPR; Β-hydroxybutyrate

DOI:  https://doi.org/10.1007/s11033-024-09754-5
Cell Rep. 2024 Jul 17. pii: S2211-1247(24)00845-3. [Epub ahead of print]43(8): 114516

Fatty acid synthesis promotes inflammasome activation through NLRP3 palmitoylation.

Stuart Leishman, Najd M Aljadeed, Liyunhe Qian, Shamshad Cockcroft, Jacques Behmoaras, Paras K Anand.

  Despite its significance, the role of lipid metabolism in NLRP3 inflammasome remains elusive. Here, we reveal a critical role for fatty acid synthase (FASN) in NLRP3 inflammasome activation. We demonstrate that pharmacological or genetic depletion of FASN dampens NLRP3 activation in primary mouse and human macrophages and in mice. This disruption in NLRP3 activation is contingent upon FASN activity. Accordingly, abolishing cellular palmitoylation, a post-translational modification in which the FASN product palmitate is reversibly conjugated to cysteine residues of target proteins, blunts inflammasome signaling. Correspondingly, an acyl-biotin exchange assay corroborated NLRP3 palmitoylation. Mechanistically, Toll-like receptor (TLR) ligation introduces palmitoylation at NLRP3 Cys898, permitting NLRP3 translocation to dispersed trans-Golgi network (dTGN) vesicles, the site of inflammasome assembly, upon NLRP3 activation. Accordingly, the NLRP3 Cys898 mutant exhibits reduced palmitoylation, limited translocation to the dTGN compartment, and diminished inflammasome activation. These results underscore mechanistic insights through which lipid metabolism licenses NLRP3 inflammasome assembly and activation.

Keywords:  CP: Immunology; CP: Metabolism; FASN; NLRP3; SREBP1; immunometabolism; inflammasome; lipid biosynthesis; lipid metabolism; palmitoylation; pyroptosis; trans Golgi network

DOI:  https://doi.org/10.1016/j.celrep.2024.114516
Am J Physiol Cell Physiol. 2024 Jul 16.

Decreased skeletal muscle intramyocellular lipid droplet-mitochondrial contact contributes to myosteatosis in cancer cachexia.

Thomas D Cardaci, Brandon N VanderVeen, Alexander R Huss, Brooke M Bullard, Kandy T Velazquez, Norma Frizzell, James A Carson, Robert L Price, E Angela Murphy.

  Cancer cachexia, the unintentional loss of lean mass, contributes to functional dependency, poor treatment outcomes, and decreased survival. While its pathogenicity is multifactorial, metabolic dysfunction remains a hallmark of cachexia. However, significant knowledge gaps exist in understanding the role of skeletal muscle lipid metabolism and dynamics in this condition. We examined skeletal muscle metabolic dysfunction, intramyocellular LD content, LD morphology and subcellular distribution, and LD-mitochondrial interactions using the Lewis Lung Carcinoma (LLC) murine model of cachexia. C57/BL6 male mice (n=20) were implanted with LLC cells [106] in the right flank or underwent PBS sham injections. Skeletal muscle was excised for transmission electron microscopy (TEM; soleus), oil red o/lipid staining (tibialis anterior), and protein (gastrocnemius). LLC mice had a greater number (232%; p=0.006) and size (130%; p=0.023) of intramyocellular LDs further supported by increased oil-red O positive (87%; p=0.0109) and 'very high' oil-red O positive (178%; p=0.0002) fibers compared to controls and this was inversely correlated with fiber size (R2=0.5294; p<0.0001). Morphological analyses of LDs show increased elongation and complexity (aspect ratio: IMF: 9%, p=0.046) with decreases in circularity (circularity: SS: 6%, p=0.042) or roundness (roundness: Whole: 10%, p=0.033; IMF: 8%, p=0.038) as well as decreased LD-mitochondria touch (-15%; p=0.006), contact length (-38%; p=0.036), and relative contact (86%; p=0.004). Further, dysregulation in lipid metabolism (adiponectin, CPT-1b) and LD-associated proteins, perilipin-2 and perilipin-5, in cachectic muscle (p<0.05) were observed. Collectively, we provide evidence that skeletal muscle myosteatosis, altered LD morphology, and decreased LD-mitochondrial interactions occur in a preclinical model of cancer cachexia.

Keywords:  Lewis Lung Carcinoma; high-fat diet; lipid deposition; lipid metabolism; muscle wasting

DOI:  https://doi.org/10.1152/ajpcell.00345.2024
Sci Am. 2023 Jun 01. 328(6): 28

Star Power: Does fusion have a future after all?

Philip Ball.

DOI: https://doi.org/10.1038/scientificamerican0623-28