bims-mimcad 2024-11-03 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024–11–03
thirteen papers selected by
Henver Brunetta, Karolinska Institutet

Reducing the mitochondrial oxidative burden alleviates lipid-induced muscle insulin resistance in humans.
Skeletal muscle from TBC1D4 p.Arg684Ter variant carriers is severely insulin resistant but exhibits normal metabolic responses during exercise.
CHK1 attenuates cardiac dysfunction via suppressing SIRT1-ubiquitination.
Integrated systems biology identifies disruptions in mitochondrial function and metabolism as key contributors to heart failure with preserved ejection fraction (HFpEF).
Pyruvate dehydrogenase kinase 1 controls triacylglycerol hydrolysis in cardiomyocytes.
Semaglutide normalizes increased cardiomyocyte calcium transients in a rat model of high fat diet-induced obesity.
ALDH2 mediates the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on improving cardiac remodeling.
The mitochondrial citrate carrier SLC25A1 regulates metabolic reprogramming and morphogenesis in the developing heart.
A hierarchical hepatic de novo lipogenesis substrate supply network utilizing pyruvate, acetate, and ketones.
Bempedoic acid suppresses diet-induced hepatic steatosis independently of ATP-citrate lyase.
TGF-β antagonism synergizes with PPARγ agonism to reduce fibrosis and enhance beige adipogenesis.
Impaired unsaturated fatty acid elongation alters mitochondrial function and accelerates metabolic dysfunction-associated steatohepatitis progression.
Shortened sleep duration impairs adipose tissue adrenergic stimulation of lipolysis in postmenopausal women.

Sci Adv. 2024 Nov;10(44): eadq4461

Reducing the mitochondrial oxidative burden alleviates lipid-induced muscle insulin resistance in humans.

Matteo Fiorenza, Johan Onslev, Carlos Henríquez-Olguín, Kaspar W Persson, Sofie A Hesselager, Thomas E Jensen, Jørgen F P Wojtaszewski, Morten Hostrup, Jens Bangsbo.

Preclinical models suggest mitochondria-derived oxidative stress as an underlying cause of insulin resistance. However, it remains unknown whether this pathophysiological mechanism is conserved in humans. Here, we used an invasive in vivo mechanistic approach to interrogate muscle insulin action while selectively manipulating the mitochondrial redox state in humans. To this end, we conducted insulin clamp studies combining intravenous infusion of a lipid overload with intake of a mitochondria-targeted antioxidant (mitoquinone). Under lipid overload, selective modulation of mitochondrial redox state by mitoquinone enhanced insulin-stimulated glucose uptake in skeletal muscle. Mechanistically, mitoquinone did not affect canonical insulin signaling but augmented insulin-stimulated glucose transporter type 4 (GLUT4) translocation while reducing the mitochondrial oxidative burden under lipid oversupply. Complementary ex vivo studies in human muscle fibers exposed to high intracellular lipid levels revealed that mitoquinone improves features of mitochondrial bioenergetics, including diminished mitochondrial H2O2 emission. These findings provide translational and mechanistic evidence implicating mitochondrial oxidants in the development of lipid-induced muscle insulin resistance in humans.

DOI: https://doi.org/10.1126/sciadv.adq4461
Nat Metab. 2024 Oct 31.

Skeletal muscle from TBC1D4 p.Arg684Ter variant carriers is severely insulin resistant but exhibits normal metabolic responses during exercise.

Jonas M Kristensen, Rasmus Kjøbsted, Trine J Larsen, Christian S Carl, Janne R Hingst, Johan Onslev, Jesper B Birk, Anette Thorup, Dorte E Steenberg, Jonas R Knudsen, Nicolai S Henriksen, Elise J Needham, Jens F Halling, Anders Gudiksen, Carsten F Rundsten, Kristian E Hanghøj, Sara E Stinson, Birgitte Hoier, Camilla C Hansen, Thomas E Jensen, Ylva Hellsten, Henriette Pilegaard, Niels Grarup, Jesper Olesen, Sean J Humphrey, David E James, Michael L Pedersen, Erik A Richter, Torben Hansen, Marit E Jørgensen, Jørgen F P Wojtaszewski.

In the Greenlandic Inuit population, 4% are homozygous carriers of a genetic nonsense TBC1D4 p.Arg684Ter variant leading to loss of the muscle-specific isoform of TBC1D4 and an approximately tenfold increased risk of type 2 diabetes1. Here we show the metabolic consequences of this variant in four female and four male homozygous carriers and matched controls. An extended glucose tolerance test reveals prolonged hyperglycaemia followed by reactive hypoglycaemia in the carriers. Whole-body glucose disposal is impaired during euglycaemic-hyperinsulinaemic clamp conditions and associates with severe insulin resistance in skeletal muscle only. Notably, a marked reduction in muscle glucose transporter GLUT4 and associated proteins is observed. While metabolic regulation during exercise remains normal, the insulin-sensitizing effect of a single exercise bout is compromised. Thus, loss of the muscle-specific isoform of TBC1D4 causes severe skeletal muscle insulin resistance without baseline hyperinsulinaemia. However, physical activity can ameliorate this condition. These observations offer avenues for personalized interventions and targeted preventive strategies.

DOI: https://doi.org/10.1038/s42255-024-01153-1
Metabolism. 2024 Oct 23. pii: S0026-0495(24)00276-2. [Epub ahead of print] 156048

CHK1 attenuates cardiac dysfunction via suppressing SIRT1-ubiquitination.

Tong-Tong Yang, Liu-Hua Zhou, Ling-Feng Gu, Ling-Ling Qian, Yu-Lin Bao, Peng Jing, Jia-Teng Sun, Chong Du, Tian-Kai Shan, Si-Bo Wang, Wen-Jing Wang, Jia-Yi Chen, Ze-Mu Wang, Hao Wang, Qi-Ming Wang, Ru-Xing Wang, Lian-Sheng Wang.

   BACKGROUND: Mitochondrial dysfunction is linked to myocardial ischemia-reperfusion (I/R) injury. Checkpoint kinase 1 (CHK1) could facilitate cardiomyocyte proliferation, however, its role on mitochondrial function in I/R injury remains unknown.
METHODS: To investigate the role of CHK1 on mitochondrial function following I/R injury, cardiomyocyte-specific knockout/overexpression mouse models were generated. Adult mouse cardiomyocytes (AMCMs) were isolated for in vitro study. Mass spectrometry-proteomics analysis and protein co-immunoprecipitation assays were conducted to dissect the molecular mechanism.
RESULTS: CHK1 was downregulated in myocardium post I/R and AMCMs post oxygen-glucose deprivation/re‑oxygenation (OGD/R). In vivo, CHK1 overexpression protected against I/R induced cardiac dysfunction, while heterogenous CHK1 knockout exacerbated cardiomyopathy. In vitro, CHK1 inhibited OGD/R-induced cardiomyocyte apoptosis and bolstered cardiomyocyte survival. Mechanistically, CHK1 attenuated oxidative stress and preserved mitochondrial metabolism in cardiomyocytes under I/R. Moreover, disrupted mitochondrial homeostasis in I/R myocardium was restored by CHK1 through the promotion of mitochondrial biogenesis and mitophagy. Through mass spectrometry analysis following co-immunoprecipitation, SIRT1 was identified as a direct target of CHK1. The 266-390 domain of CHK1 interacted with the 160-583 domain of SIRT1. Importantly, CHK1 phosphorylated SIRT1 at Thr530 residue, thereby inhibiting SMURF2-mediated degradation of SIRT1. The role of CHK1 in maintaining mitochondrial dynamics control and myocardial protection is abolished by SIRT1 inhibition, while inactivated mutation of SIRT1 Thr530 fails to reverse the impaired mitochondrial dynamics following CHK1 knockdown. CHK1 Δ390 amino acids (aa) mutant functioned similarly to full-length CHK1 in scavenging ROS and maintaining mitochondrial dynamics. Consistently, cardiac-specific SIRT1 knockdown attenuated the protective role of CHK1 in I/R injury.
CONCLUSIONS: Our findings revealed that CHK1 mitigates I/R injury and restores mitochondrial dynamics in cardiomyocytes through a SIRT1-dependent mechanism.

Keywords:  CHK1; Cardiac dysfunction; Mitochondrial quality control; SIRT1; Ubiquitination

DOI:  https://doi.org/10.1016/j.metabol.2024.156048
bioRxiv. 2024 Oct 25. pii: 2024.10.25.619450. [Epub ahead of print]

Integrated systems biology identifies disruptions in mitochondrial function and metabolism as key contributors to heart failure with preserved ejection fraction (HFpEF).

Andrew A Gibb, Kyle LaPenna, Ryan B Gaspar, Nadina R Latchman, Yinfei Tan, Carmen Choya-Foces, Jake E Doiron, Zhen Li, Huijing Xia, Michael P Lazaropoulos, Mariell Conwell, Thomas E Sharp, Traci T Goodchild, David J Lefer, John W Elrod.

Background: Heart failure with preserved ejection fraction (HFpEF) accounts for ∼50% of HF cases, with no effective treatments. The ZSF1-obese rat model recapitulates numerous clinical features of HFpEF including hypertension, obesity, metabolic syndrome, exercise intolerance, and LV diastolic dysfunction. Here, we utilized a systems-biology approach to define the early metabolic and transcriptional signatures to gain mechanistic insight into the pathways contributing to HFpEF development.
Methods: Male ZSF1-obese, ZSF1-lean hypertensive controls, and WKY (wild-type) controls were compared at 14w of age for extensive physiological phenotyping and LV tissue harvesting for unbiased metabolomics, RNA-sequencing, and assessment of mitochondrial morphology and function. Utilizing ZSF1-lean and WKY controls enabled a distinction between hypertension-driven molecular changes contributing to HFpEF pathology, versus hypertension + metabolic syndrome.
Results: ZSF1-obese rats displayed numerous clinical features of HFpEF. Comparison of ZSF1-lean vs WKY (i.e., hypertension-exclusive effects) revealed metabolic remodeling suggestive of increased aerobic glycolysis, decreased β-oxidation, and dysregulated purine and pyrimidine metabolism with few transcriptional changes. ZSF1-obese rats displayed worsened metabolic remodeling and robust transcriptional remodeling highlighted by the upregulation of inflammatory genes and downregulation of the mitochondrial structure/function and cellular metabolic processes. Integrated network analysis of metabolomic and RNAseq datasets revealed downregulation of nearly all catabolic pathways contributing to energy production, manifesting in a marked decrease in the energetic state (i.e., reduced ATP/ADP, PCr/ATP). Cardiomyocyte ultrastructure analysis revealed decreased mitochondrial area, size, and cristae density, as well as increased lipid droplet content in HFpEF hearts. Mitochondrial function was also impaired as demonstrated by decreased substrate-mediated respiration and dysregulated calcium handling.
Conclusions: Collectively, the integrated omics approach applied here provides a framework to uncover novel genes, metabolites, and pathways underlying HFpEF, with an emphasis on mitochondrial energy metabolism as a potential target for intervention.

DOI: https://doi.org/10.1101/2024.10.25.619450
bioRxiv. 2024 Oct 14. pii: 2024.10.14.618123. [Epub ahead of print]

Pyruvate dehydrogenase kinase 1 controls triacylglycerol hydrolysis in cardiomyocytes.

Michael G Atser, Chelsea D Wenyonu, Elyn M Rowe, Connie L K Leung, Haoning Howard Cen, Eric D Queathem, Leo T Liu, Renata Moravcova, Jason Rogalski, David Perrin, Peter Crawford, Leonard J Foster, Armando Alcazar, James D Johnson.

  Pyruvate dehydrogenase kinase (PDK) 1 is one of four isozymes that inhibit the oxidative decarboxylation of pyruvate to acetyl-CoA via pyruvate dehydrogenase. PDK activity is elevated in fasting or starvation conditions to conserve carbohydrate reserves. PDK has also been shown to increase mitochondrial fatty acid utilization. In cardiomyocytes, metabolic flexibility is crucial for the fulfillment of high energy requirements. The PDK1 isoform is abundant in cardiomyocytes, but its specific contribution to cardiomyocyte metabolism is unclear. Here we show that PDK1 regulates cardiomyocyte fuel preference by mediating triacylglycerol turnover in differentiated H9c2 myoblasts using lentiviral shRNA to knockdown Pdk1. Somewhat surprisingly, PDK1 loss did not affect overall PDH activity, basal glycolysis, or glucose oxidation revealed by oxygen consumption rate experiments and 13C6 glucose labelling. On the other hand, we observed decreased triacylglycerol turnover in H9c2 cells with PDK1 knockdown, which was accompanied by decreased mitochondrial fatty acid utilization following nutrient deprivation. 13C16 palmitate tracing of uniformly labelled acyl chains revealed minimal acyl chain shuffling within triacylglycerol, indicating that the triacylglycerol hydrolysis, and not re-esterification, was dysfunctional in PDK1 suppressed cells. Importantly, PDK1 loss did not significantly impact the cellular lipidome or triacylglycerol accumulation following palmitic acid treatment, suggesting that effects of PDK1 on lipid metabolism were specific to the nutrient-deprived state. We validated that PDK1 loss decreased triacylglycerol turnover in Pdk1 knockout mice. Together, these findings implicate a novel role for PDK1 in lipid metabolism in cardiomyocytes, independent of its canonical roles in glucose metabolism.

Keywords:  carbohydrate metabolism; cardiac metabolism; lipid metabolism; pyruvate dehydrogenase kinase; triacylglycerol

DOI:  https://doi.org/10.1101/2024.10.14.618123
ESC Heart Fail. 2024 Oct 31.

Semaglutide normalizes increased cardiomyocyte calcium transients in a rat model of high fat diet-induced obesity.

Vasco Sequeira, Julia Theisen, Katharina J Ermer, Marie Oertel, Anton Xu, David Weissman, Katharina Ecker, Jan Dudek, Martin Fassnacht, Alexander Nickel, Michael Kohlhaas, Christoph Maack, Ulrich Dischinger.

   AIMS: Obesity increases the risk of heart failure with preserved (HFpEF), but not reduced ejection fraction (HFrEF). The glucagon-like peptide-1 receptor agonist (GLP-1-RA) semaglutide improves outcome of patients with obesity with or without HFpEF, while GLP-1-RAs were associated with adverse outcome in patients with HFrEF. Here, we investigate the effect of in vivo treatment with semaglutide on excitation-contraction coupling in a rat model of obesity.
METHODS AND RESULTS: Rats received high-fat/high-fructose diet for 8 weeks and were then randomized to semaglutide (HFD/Sema) or vehicle (HFD/Veh) for another 8 weeks, during which they could choose between HFD and a low-fat/high-fructose diet (LFD). Control rats received either standard chow (CON), HFD or LFD only, without treatment. After 16 weeks, sarcomere shortening and cytosolic Ca2+ concentrations ([Ca2+]c) were determined in isolated cardiomyocytes. Compared with CON, HFD/Veh increased the amplitude of [Ca2+]c transients and systolic sarcomere shortening in absence or presence of β-adrenergic stimulation, which was reversed by HFD/Sema. Caffeine-induced sarcoplasmic reticulum (SR) Ca2+ release and L-type Ca2+ channel (LTCC) currents were reduced by HFD/Sema versus HFD/Veh, while SR Ca2+ ATPase activity remained unaffected. Compared with HFD, LFD increased [Ca2+]c transients and sarcomere shortening further despite similar effects on body weight.
CONCLUSIONS: While HFD increased cardiomyocyte [Ca2+]c transients and systolic sarcomere shortening, semaglutide normalized these alterations, mediated by reduced SR Ca2+ load and LTCC currents. Because increased LTCC currents were previously traced to cardiac hypertrophy, these effects may explain why GLP-1-RAs provide benefits for patients with obesity with or without HFpEF, but rather adverse outcome in HFrEF.

Keywords:  Excitation‐contraction coupling; Glucagon‐like peptide agonists; Heart failure; Obesity; Semaglutide

DOI:  https://doi.org/10.1002/ehf2.15152
Cardiovasc Diabetol. 2024 Oct 26. 23(1): 380

ALDH2 mediates the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on improving cardiac remodeling.

Han Liu, Bingchen Jiang, Rui Hua, Xuehao Liu, Bao Qiao, Xiangxin Zhang, Xilong Liu, Wenjun Wang, Qiuhuan Yuan, Bailu Wang, Shujian Wei, Yuguo Chen.

   BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are now recommended for patients with heart failure, but the mechanisms that underlie the protective role of SGLT2i in cardiac remodeling remain unclear. Aldehyde dehydrogenase 2 (ALDH2) effectively prevents cardiac remodeling. Here, the key role of ALDH2 in the efficacy of SGLT2i on cardiac remodeling was studied.
METHODS: Analysis of multiple transcriptomic datasets and two-sample Mendelian randomization were performed to find out the differentially expressed genes between pathological cardiac hypertrophy models (patients) and controls. A pathological cardiac hypertrophy mouse model was established via transverse aortic constriction (TAC) or isoproterenol (ISO). Cardiomyocyte-specific ALDH2 knockout mice (ALDH2CMKO) and littermate control mice (ALDH2flox/flox) were generated to determine the critical role of ALDH2 in the preventive effects of dapagliflozin (DAPA) on cardiac remodeling. RNA sequencing, gene knockdown or overexpression, bisulfite sequencing PCR, and luciferase reporter assays were performed to explore the underlying molecular mechanisms involved.
RESULTS: Only ALDH2 was differentially expressed when the differentially expressed genes obtained via Mendelian analysis and the differentially expressed genes obtained from the multiple transcriptome datasets were combined. Mendelian analysis revealed that ALDH2 was negatively related to the severity of myocardial hypertrophy in patients. DAPA alleviated cardiac remodeling in mouse hearts subjected to TAC or ISO. ALDH2 expression was reduced, whereas ALDH2 expression was restored by DAPA in hypertrophic hearts. Cardiomyocyte specific ALDH2 knockout abolished the protective role of DAPA in preventing cardiac remodeling. ALDH2 expression and activity were increased in DAPA-treated neonatal rat primary cardiomyocytes (NRCMs), H9C2 cells and AC16 cells. Moreover, DAPA upregulated ALDH2 in peripheral blood mononuclear cells (PBMCs) from patients with type 2 diabetes. Sodium/proton exchanger 1 (NHE1) inhibition contributed to the regulation of ALDH2 by DAPA. DAPA suppressed the production of reactive oxygen species (ROS), downregulated DNA methyltransferase 1 (DNMT1) and subsequently reduced the ALDH2 promoter methylation level. Further studies revealed that DAPA enhanced the binding of nuclear transcription factor Y, subunit A (NFYA) to the promoter region of ALDH2, which was due to the decreased promoter methylation level of ALDH2.
CONCLUSIONS: The upregulation of ALDH2 plays a critical role in the protection of DAPA against cardiac remodeling. DAPA enhances the binding of NFYA to the ALDH2 promoter by reducing the ALDH2 promoter methylation level through NHE1/ROS/DNMT1 pathway.

Keywords:  Aldehyde dehydrogenase 2; Cardiac remodeling; Methylation; Sodium-glucose cotransporter-2 inhibitors; Sodium/proton exchanger 1

DOI:  https://doi.org/10.1186/s12933-024-02477-8
Commun Biol. 2024 Oct 31. 7(1): 1422

The mitochondrial citrate carrier SLC25A1 regulates metabolic reprogramming and morphogenesis in the developing heart.

Chiemela Ohanele, Jessica N Peoples, Anja Karlstaedt, Joshua T Geiger, Ashley D Gayle, Nasab Ghazal, Fateemaa Sohani, Milton E Brown, Michael E Davis, George A Porter, Victor Faundez, Jennifer Q Kwong.

The developing mammalian heart undergoes an important metabolic shift from glycolysis towards mitochondrial oxidation that is critical to support the increasing energetic demands of the maturing heart. Here, we describe a new mechanistic link between mitochondria and cardiac morphogenesis, uncovered by studying mitochondrial citrate carrier (SLC25A1) knockout mice. Slc25a1 null embryos displayed impaired growth, mitochondrial dysfunction and cardiac malformations that recapitulate the congenital heart defects observed in 22q11.2 deletion syndrome, a microdeletion disorder involving the SLC25A1 locus. Importantly, Slc25a1 heterozygous embryos, while overtly indistinguishable from wild type, exhibited an increased frequency of these defects, suggesting Slc25a1 haploinsuffiency and dose-dependent effects. Mechanistically, SLC25A1 may link mitochondria to transcriptional regulation of metabolism through epigenetic control of gene expression to promote metabolic remodeling in the developing heart. Collectively, this work positions SLC25A1 as a novel mitochondrial regulator of cardiac morphogenesis and metabolic maturation, and suggests a role in congenital heart disease.

DOI: https://doi.org/10.1038/s42003-024-07110-8
Cell Metab. 2024 Oct 25. pii: S1550-4131(24)00409-1. [Epub ahead of print]

A hierarchical hepatic de novo lipogenesis substrate supply network utilizing pyruvate, acetate, and ketones.

Adam J Rauckhorst, Ryan D Sheldon, Daniel J Pape, Adnan Ahmed, Kelly C Falls-Hubert, Ronald A Merrill, Reid F Brown, Kshitij Deshmukh, Thomas A Vallim, Stanislaw Deja, Shawn C Burgess, Eric B Taylor.

  Hepatic de novo lipogenesis (DNL) is a fundamental physiologic process that is often pathogenically elevated in metabolic disease. Treatment is limited by incomplete understanding of the metabolic pathways supplying cytosolic acetyl-CoA, the obligate precursor to DNL, including their interactions and proportional contributions. Here, we combined extensive 13C tracing with liver-specific knockout of key mitochondrial and cytosolic proteins mediating cytosolic acetyl-CoA production. We show that the mitochondrial pyruvate carrier (MPC) and ATP-citrate lyase (ACLY) gate the major hepatic lipogenic acetyl-CoA production pathway, operating in parallel with acetyl-CoA synthetase 2 (ACSS2). Given persistent DNL after mitochondrial citrate carrier (CiC) and ACSS2 double knockout, we tested the contribution of exogenous and leucine-derived acetoacetate to acetoacetyl-CoA synthetase (AACS)-dependent DNL. CiC knockout increased acetoacetate-supplied hepatic acetyl-CoA production and DNL, indicating that ketones function as mitochondrial-citrate reciprocal DNL precursors. By delineating a mitochondrial-cytosolic DNL substrate supply network, these findings may inform strategies to therapeutically modulate DNL.

Keywords:  AACS; ACLY; ACSS2; ATP-citrate lyase; CiC; DNL; MPC; acetoacetyl-CoA synthetase; acetyl-CoA synthetase 2; de novo lipogenesis; liver; metabolomics; mitochondrial citrate carrier; mitochondrial pyruvate carrier; stable isotope tracers

DOI:  https://doi.org/10.1016/j.cmet.2024.10.013
Cell Metab. 2024 Oct 26. pii: S1550-4131(24)00410-8. [Epub ahead of print]

Bempedoic acid suppresses diet-induced hepatic steatosis independently of ATP-citrate lyase.

Joyce Y Liu, Ramya S Kuna, Laura V Pinheiro, Phuong T T Nguyen, Jaclyn E Welles, Jack M Drummond, Nivitha Murali, Prateek Sharma, Julianna G Supplee, Mia Shiue, Steven Zhao, Aimee T Farria, Avi Kumar, Mauren L Ruchhoeft, Christina Demetriadou, Daniel S Kantner, Adam Chatoff, Emily Megill, Paul M Titchenell, Nathaniel W Snyder, Christian M Metallo, Kathryn E Wellen.

  ATP citrate lyase (ACLY) synthesizes acetyl-CoA for de novo lipogenesis (DNL), which is elevated in metabolic dysfunction-associated steatotic liver disease. Hepatic ACLY is inhibited by the LDL-cholesterol-lowering drug bempedoic acid (BPA), which also improves steatosis in mice. While BPA potently suppresses hepatic DNL and increases fat catabolism, it is unclear if ACLY is its primary molecular target in reducing liver triglyceride. We show that on a Western diet, loss of hepatic ACLY alone or together with the acetyl-CoA synthetase ACSS2 unexpectedly exacerbates steatosis, linked to reduced PPARα target gene expression and fatty acid oxidation. Importantly, BPA treatment ameliorates Western diet-mediated triacylglyceride accumulation in both WT and liver ACLY knockout mice, indicating that its primary effects on hepatic steatosis are ACLY independent. Together, these data indicate that hepatic ACLY plays an unexpected role in restraining diet-dependent lipid accumulation and that BPA exerts substantial effects on hepatic lipid metabolism independently of ACLY.

Keywords:  ACLY; ACSS2; PPARα; bempedoic acid; lipid metabolism; metabolic dysfunction-associated steatotic liver disease

DOI:  https://doi.org/10.1016/j.cmet.2024.10.014
Mol Metab. 2024 Oct 24. pii: S2212-8778(24)00185-6. [Epub ahead of print] 102054

TGF-β antagonism synergizes with PPARγ agonism to reduce fibrosis and enhance beige adipogenesis.

Young Jae Bahn, Yanling Wang, Pradeep Dagur, Nicholas Scott, Cheryl Cero, Kelly T Long, Nhuquynh Nguyen, Aaron M Cypess, Sushil G Rane.

   OBJECTIVE: Adipose tissue depots vary markedly in their ability to store and metabolize triglycerides, undergo beige adipogenesis and susceptibility to metabolic disease. The molecular mechanisms that underlie such heterogeneity are not entirely clear. Previously, we showed that TGF-β signaling suppresses beige adipogenesis via repressing the recruitment of dedicated beige progenitors. Here, we find that TGF-β signals dynamically regulate the balance between adipose tissue fibrosis and beige adipogenesis.
METHODS: We investigated adipose tissue depot-specific differences in activation of TGF-β signaling in response to dietary challenge. RNA-seq and fluorescence activated cell sorting was performed to identify and characterize cells responding to changes in TGF-β signaling status. Mouse models, pharmacological strategies and human adipose tissue analyses were performed to further define the influence of TGF-β signaling on fibrosis and functional beige adipogenesis.
RESULTS: Elevated basal and high-fat diet inducible activation of TGF-β/Smad3 signaling was observed in the visceral adipose tissue depot. Activation of TGF-β/Smad3 signaling was associated with increased adipose tissue fibrosis. RNA-seq combined with fluorescence-activated cell sorting of stromal vascular fraction of epididymal white adipose tissue depot resulted in identification of TGF-β/Smad3 regulated ITGA5+ fibrogenic progenitors. TGF-β/Smad3 signal inhibition, genetically or pharmacologically, reduced fibrosis and increased functional beige adipogenesis. TGF-β/Smad3 antagonized the beneficial effects of PPARγ whereas TGF-β receptor 1 inhibition synergized with actions of rosiglitazone, a PPARγ agonist, to dampen fibrosis and promote beige adipogenesis. Positive correlation between TGF-β activation and ITGA5 was observed in human adipose tissue, with visceral adipose tissue depots exhibiting higher fibrosis potential than subcutaneous or brown adipose tissue depots.
CONCLUSIONS: Basal and high-fat diet inducible activation of TGF-β underlies the heterogeneity of adipose tissue depots. TGF-β/Smad3 activation promotes adipose tissue fibrosis and suppresses beige progenitors. Together, these dual mechanisms preclude functional beige adipogenesis. Controlled inhibition of TβR1 signaling and concomitant PPARγ stimulation can suppress adipose tissue fibrosis and promote beige adipogenesis to improve metabolism.

Keywords:  Beige adipogenesis; PPARγ; Smad3; TGF-β; fibrosis; metabolism; rosiglitazone

DOI:  https://doi.org/10.1016/j.molmet.2024.102054
Metabolism. 2024 Oct 23. pii: S0026-0495(24)00279-8. [Epub ahead of print]162 156051

Impaired unsaturated fatty acid elongation alters mitochondrial function and accelerates metabolic dysfunction-associated steatohepatitis progression.

Adrien Vouilloz, Thibaut Bourgeois, Marc Diedisheim, Thomas Pilot, Antoine Jalil, Naig Le Guern, Victoria Bergas, Noéline Rohmer, Florence Castelli, Damien Leleu, Alexis Varin, Jean-Paul Pais de Barros, Pascal Degrace, Mickael Rialland, Camille Blériot, Nicolas Venteclef, Charles Thomas, David Masson.

   BACKGROUND AND AIMS: Although qualitative and quantitative alterations in liver Polyunsaturated Fatty Acids (PUFAs) are observed in MASH in humans, a causal relationship of PUFAs biosynthetic pathways is yet to be clarified. ELOVL5, an essential enzyme in PUFA elongation regulates hepatic triglyceride metabolism. Nonetheless, the long-term consequences of elongase disruption, particularly in murine models of MASH, have not been evaluated.
APPROACH & RESULTS: In humans, transcriptomic data indicated that PUFAs biosynthesis enzymes and notably ELOVL5 were induced during MASH progression. Moreover, gene module association determination revealed that ELOVL5 expression was associated with mitochondrial function in both humans and mice. WT and Elovl5-deficient mice were fed a high-fat, high-sucrose (HF/HS) diet for four months. Elovl5 deficiency led to limited systemic metabolic alterations but significant hepatic phenotype was observed in Elovl5-/- mice after the HF/HS diet, including hepatomegaly, pronounced macrovesicular and microvesicular steatosis, hepatocyte ballooning, immune cell infiltration, and fibrosis. Lipid analysis confirmed hepatic triglyceride accumulation and a reshaping of FA profile. Transcriptomic analysis indicated significant upregulation of genes involved in immune cell recruitment and fibrosis, and downregulation of genes involved in oxidative phosphorylation in Elovl5-/- mice. Alterations of FA oxidation and energy metabolism were confirmed by non-targeted metabolomic approach. Analysis of mitochondrial function in Elovl5-/- mice showed morphological alterations, qualitative cardiolipin changes with an enrichment in species containing shorter unsaturated FAs, and decreased activity of I and III respiratory chain complexes.
CONCLUSION: Enhanced susceptibility to diet-induced MASH and fibrosis in Elovl5-/- mice is intricately associated with disruptions in mitochondrial homeostasis, stemming from a profound reshaping of mitochondrial lipids, notably cardiolipins.

Keywords:  Cardiolipins; ELOVL5; MASH; MASLD; PUFAs; Steatosis

DOI:  https://doi.org/10.1016/j.metabol.2024.156051
Obesity (Silver Spring). 2024 Oct 27.

Shortened sleep duration impairs adipose tissue adrenergic stimulation of lipolysis in postmenopausal women.

Prachi Singh, Robbie A Beyl, Jacqueline M Stephens, Allison J Richard, Anik Boudreau, R Caitlin Hebert, Robert C Noland, David H Burk, Sujoy Ghosh, Jaroslaw Staszkiewicz, J Michael Salbaum, Josiane L Broussard, Marie-Pierre St-Onge, Eric Ravussin, Kara L Marlatt.

OBJECTIVE: The objective of this study was to examine the changes in adipose tissue lipolytic capacity and insulin signaling in response to shortened sleep duration (SSD) in postmenopausal women.
METHODS: Adipose tissue from a randomized crossover study of nine healthy postmenopausal women (mean [SD], age: 59 [4] years; BMI: 28.0 [2.6] kg/m2) exposed to four nights of habitual and SSD (60% of habitual sleep) while following a eucaloric diet was examined ex vivo. Tissue lipolytic capacity was determined by measurement of secreted glycerol. Cellular insulin signaling was determined by measuring insulin-mediated changes in Akt phosphorylation. RNA sequencing examined global transcriptional changes.
RESULTS: With SSD, basal glycerol secretion was reduced, and isoproterenol-stimulated lipolysis was attenuated. Insulin concentration-dependent increases in phosphorylated Akt observed in samples after habitual sleep were abrogated after SSD. However, insulin-mediated suppression of lipolysis remained unaltered with changes in sleep duration. Increased transcription of genes involved in adipogenesis and fatty acid metabolism was observed after SSD.
CONCLUSIONS: SSD blunts adrenergic stimulation of lipolysis without altering insulin-mediated suppression of lipolysis in postmenopausal women. These changes in adipose tissue may potentiate fat gain independent of caloric intake. Therefore, interventions promoting sleep may be considered to mitigate abdominal adiposity in postmenopausal women.

DOI: https://doi.org/10.1002/oby.24162