bims-obesme 2024-06-02 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2024–06–02
fourteen papers selected by
Xiong Weng, University of Edinburgh

Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels.
Loss of Bcl-3 regulates macrophage polarization by promoting macrophage glycolysis.
The novel adrenergic agonist ATR-127 targets skeletal muscle and brown adipose tissue to tackle diabesity and steatohepatitis.
Rab30 facilitates lipid homeostasis during fasting.
Pancreatic beta-cell IL-22 receptor deficiency induces age-dependent dysregulation of insulin biosynthesis and systemic glucose homeostasis.
Regulation of hepatic lipogenesis by asymmetric arginine methylation.
Hippo-YAP/TAZ signalling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass.
Inhibition of hepatic p63 ameliorates steatohepatitis with fibrosis in mice.
Early life interventions metformin and trodusquemine metabolically reprogram the developing mouse liver through transcriptomic alterations.
Liver-specific Lxr inhibition represses reverse cholesterol transport in cholesterol-fed mice.
Hippo and PI5P4K signaling intersect to control the transcriptional activation of YAP.
HSDL2 links nutritional cues to bile acid and cholesterol homeostasis.
Gut bacteria convert glucocorticoids into progestins in the presence of hydrogen gas.
SGLT2 inhibition eliminates senescent cells and alleviates pathological aging.

Nat Commun. 2024 May 30. 15(1): 4605

Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels.

Shuai Yan, Anna Santoro, Micah J Niphakis, Antonio M Pinto, Christopher L Jacobs, Rasheed Ahmad, Radu M Suciu, Bryan R Fonslow, Rachel A Herbst-Graham, Nhi Ngo, Cassandra L Henry, Dylan M Herbst, Alan Saghatelian, Barbara B Kahn, Evan D Rosen.

Obesity-induced inflammation causes metabolic dysfunction, but the mechanisms remain elusive. Here we show that the innate immune transcription factor interferon regulatory factor (IRF3) adversely affects glucose homeostasis through induction of the endogenous FAHFA hydrolase androgen induced gene 1 (AIG1) in adipocytes. Adipocyte-specific knockout of IRF3 protects male mice against high-fat diet-induced insulin resistance, whereas overexpression of IRF3 or AIG1 in adipocytes promotes insulin resistance on a high-fat diet. Furthermore, pharmacological inhibition of AIG1 reversed obesity-induced insulin resistance and restored glucose homeostasis in the setting of adipocyte IRF3 overexpression. We, therefore, identify the adipocyte IRF3/AIG1 axis as a crucial link between obesity-induced inflammation and insulin resistance and suggest an approach for limiting the metabolic dysfunction accompanying obesity.

DOI: https://doi.org/10.1038/s41467-024-48220-5
Immunol Cell Biol. 2024 May 28.

Loss of Bcl-3 regulates macrophage polarization by promoting macrophage glycolysis.

Shengnan Liu, Hao Wang, Jiaoyang Li, Jingtao Gao, Li Yu, Xiaofei Wei, Mengchao Cui, Yuxin Zhao, Yinming Liang, Hui Wang.

  M1/M2 macrophage polarization plays an important role in regulating the balance of the microenvironment within tissues. Moreover, macrophage polarization involves the reprogramming of metabolism, such as glucose and lipid metabolism. Transcriptional coactivator B-cell lymphoma-3 (Bcl-3) is an atypical member of the IκB family that controls inflammatory factor levels in macrophages by regulating nuclear factor kappa B pathway activation. However, the relationship between Bcl-3 and macrophage polarization and metabolism remains unclear. In this study, we show that the knockdown of Bcl-3 in macrophages can regulate glycolysis-related gene expression by promoting the activation of the nuclear factor kappa B pathway. Furthermore, the loss of Bcl-3 was able to promote the interferon gamma/lipopolysaccharide-induced M1 macrophage polarization by accelerating glycolysis. Taken together, these results suggest that Bcl-3 may be a candidate gene for regulating M1 polarization in macrophages.

Keywords:  Bcl‐3; glucose metabolism; inflammation; macrophages; polarization

DOI:  https://doi.org/10.1111/imcb.12785
Mol Metab. 2024 May 17. pii: S2212-8778(24)00062-0. [Epub ahead of print] 101931

The novel adrenergic agonist ATR-127 targets skeletal muscle and brown adipose tissue to tackle diabesity and steatohepatitis.

Emanuela Talamonti, Jelena Davegardh, Anastasia Kalinovich, Sten M M van Beek, Nodi Dehvari, Carina Halleskog, Hamza M Bokhari, Dana S Hutchinson, Seungmin Ham, Laura J Humphrys, Nicola C Dijon, Aikaterini Motso, Anna Sandstrom, Evelyn Zacharewicz, Ilga Mutule, Edgars Suna, Jana Spura, Karolina Ditrychova, Leigh A Stoddart, Nicholas D Holliday, Shane C Wright, Volker M Lauschke, Soren Nielsen, Camilla Scheele, Elizabeth Cheesman, Joris Hoeks, Peter Molenaar, Roger J Summers, Benjamin Pelcman, Gopala K Yakala, Tore Bengtsson.

   OBJECTIVE: Simultaneous activation of β2- and β3-adrenoceptors (ARs) improves whole-body metabolism via beneficial effects in skeletal muscle and brown adipose tissue (BAT). Nevertheless, high-efficacy agonists simultaneously targeting these receptors whilst limiting activation of β1-ARs - and thus inducing cardiovascular complications - are currently non-existent. Therefore, we here developed and evaluated the therapeutic potential of a novel β2-and β3-AR, named ATR-127, for the treatment of obesity and its associated metabolic perturbations in preclinical models.
METHODS: In the developmental phase, we assessed the impact of ATR-127's on cAMP accumulation in relation to the non-selective β-AR agonist isoprenaline across various rodent β-AR subtypes, including neonatal rat cardiomyocytes. Following these experiments, L6 muscle cells were stimulated with ATR-127 to assess the impact on GLUT4-mediated glucose uptake and intramyocellular cAMP accumulation. Additionally, in vitro, and in vivo assessments are conducted to measure ATR-127's effects on BAT glucose uptake and thermogenesis. Finally, diet-induced obese mice were treated with 5 mg/kg ATR-127 for 21 days to investigate the effects on glucose homeostasis, body weight, fat mass, skeletal muscle glucose uptake, BAT thermogenesis and hepatic steatosis.
RESULTS: Exposure of L6 muscle cells to ATR-127 robustly enhanced GLUT4-mediated glucose uptake despite low intramyocellular cAMP accumulation. Similarly, ATR-127 markedly increased BAT glucose uptake and thermogenesis both in vitro and in vivo. Prolonged treatment of diet-induced obese mice with ATR-127 dramatically improved glucose homeostasis, an effect accompanied by decreases in body weight and fat mass. These effects were paralleled by an enhanced skeletal muscle glucose uptake, BAT thermogenesis, and improvements in hepatic steatosis.
CONCLUSIONS: Our results demonstrate that ATR-127 is a highly effective, novel β2- and β3-ARs agonist holding great therapeutic promise for the treatment of obesity and its comorbidities, whilst potentially limiting cardiovascular complications. As such, the therapeutic effects of ATR-127 should be investigated in more detail in clinical studies.

Keywords:  Hepatic steatosis; Obesity; Skeletal muscle; Type 2 diabetes; β-Adrenergic agonists

DOI:  https://doi.org/10.1016/j.molmet.2024.101931
Nat Commun. 2024 May 25. 15(1): 4469

Rab30 facilitates lipid homeostasis during fasting.

Danielle M Smith, Brian Y Liu, Michael J Wolfgang.

To facilitate inter-tissue communication and the exchange of proteins, lipoproteins, and metabolites with the circulation, hepatocytes have an intricate and efficient intracellular trafficking system regulated by small Rab GTPases. Here, we show that Rab30 is induced in the mouse liver by fasting, which is amplified in liver-specific carnitine palmitoyltransferase 2 knockout mice (Cpt2L-/-) lacking the ability to oxidize fatty acids, in a Pparα-dependent manner. Live-cell super-resolution imaging and in vivo proximity labeling demonstrates that Rab30-marked vesicles are highly dynamic and interact with proteins throughout the secretory pathway. Rab30 whole-body, liver-specific, and Rab30; Cpt2 liver-specific double knockout (DKO) mice are viable with intact Golgi ultrastructure, although Rab30 deficiency in DKO mice suppresses the serum dyslipidemia observed in Cpt2L-/- mice. Corresponding with decreased serum triglyceride and cholesterol levels, DKO mice exhibit decreased circulating but not hepatic ApoA4 protein, indicative of a trafficking defect. Together, these data suggest a role for Rab30 in the selective sorting of lipoproteins to influence hepatocyte and circulating triglyceride levels, particularly during times of excessive lipid burden.

DOI: https://doi.org/10.1038/s41467-024-48959-x
Nat Commun. 2024 May 29. 15(1): 4527

Pancreatic beta-cell IL-22 receptor deficiency induces age-dependent dysregulation of insulin biosynthesis and systemic glucose homeostasis.

Haressh Sajiir, Kuan Yau Wong, Alexandra Müller, Sahar Keshvari, Lucy Burr, Elena Aiello, Teresa Mezza, Andrea Giaccari, Guido Sebastiani, Francesco Dotta, Grant A Ramm, Graeme A Macdonald, Michael A McGuckin, Johannes B Prins, Sumaira Z Hasnain.

The IL-22RA1 receptor is highly expressed in the pancreas, and exogenous IL-22 has been shown to reduce endoplasmic reticulum and oxidative stress in human pancreatic islets and promote secretion of high-quality insulin from beta-cells. However, the endogenous role of IL-22RA1 signaling on these cells remains unclear. Here, we show that antibody neutralisation of IL-22RA1 in cultured human islets leads to impaired insulin quality and increased cellular stress. Through the generation of mice lacking IL-22ra1 specifically on pancreatic alpha- or beta-cells, we demonstrate that ablation of murine beta-cell IL-22ra1 leads to similar decreases in insulin secretion, quality and islet regeneration, whilst increasing islet cellular stress, inflammation and MHC II expression. These changes in insulin secretion led to impaired glucose tolerance, a finding more pronounced in female animals compared to males. Our findings attribute a regulatory role for endogenous pancreatic beta-cell IL-22ra1 in insulin secretion, islet regeneration, inflammation/cellular stress and appropriate systemic metabolic regulation.

DOI: https://doi.org/10.1038/s41467-024-48320-2
Metabolism. 2024 May 23. pii: S0026-0495(24)00165-3. [Epub ahead of print]157 155938

Regulation of hepatic lipogenesis by asymmetric arginine methylation.

Hye-Sook Han, Byeong Hun Choi, Seo Young Jang, Seri Choi, Geum-Sook Hwang, Seung-Hoi Koo.

   BACKGROUND AND AIMS: Hepatic lipogenesis is elevated in nutrient abundant conditions to convert the excess carbohydrate into triacylglycerol (TAG). Fatty acyl moiety of TAG is eventually transported into adipose tissues by very low density lipoprotein, leading to the accumulation of TAG as a preferred storage form of excess energy. Disruption of the balance between TAG clearance and synthesis leads to the accumulation of lipids in the liver, leading to the progression of non-alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis. Protein arginine methyltransferase (PRMT) 6 has been linked to the various metabolic processes including hepatic gluconeogenesis, muscle atrophy and lipodystrophy in mouse models. However, the role of PRMT6 in the control of hepatic lipogenesis has not been elucidated to date.
METHODS: We assessed the interaction between PRMT6 and LXR alpha by using co-immunoprecipitation assay. The specific arginine residue of LXR alpha that is methylated by PRMT6 was assessed by LC-MS/MS assay and the functional consequences of LXR alpha methylation was explored by mSREBP-1c luciferase assay. The effect of PRMT6 on hepatic lipogenesis was assessed by adenovirus-mediated ectopic expression of PRMT6 or knockdown of PRMT6 via shRNA in hepatocytes. Finally, the role of PRMT6 in hepatic lipid metabolism in vivo was explored by either ectopic expression of LXR alpha mutant that is defective in PRMT6-mediated arginine methylation or knockdown of PRMT6 in liver.
RESULTS: We found that promoter activity of sterol regulatory element binding protein (SREBP) 1c is robustly activated by PRMT6. Interestingly, we demonstrated that PRMT6 binds to LXR alpha, a transcription factor for SREBP-1c, via its LXXLL motif, leading to the asymmetric dimethylation of an arginine residue and activation of this protein. Indeed, ectopic expression of PRMT6 in hepatocytes led to the enhanced expression of LXR alpha target genes in the lipogenic pathway. Conversely, genetic or pharmacological inhibition of PRMT6 diminished expression of lipogenic genes and the lipid accumulation in primary hepatocytes. Mechanistically, we found that asymmetric dimethylation of LXR alpha led to the dissociation of small heterodimer partner (SHP), a transcriptional co-inhibitor of this factor, resulting in the activation of LXR alpha-mediated transcriptional process. Finally, we showed that disruption of asymmetric dimethylation of LXR alpha in the liver led to the diminished expression of genes in the lipogenesis, resulting in the reduced hepatic lipid accumulation in high fat diet-fed mice in vivo.
CONCLUSIONS: We showed that PRMT6 modulates LXR alpha activity by conferring asymmetric dimethylation of arginine 253, thus blocking SHP-mediated inhibition and promoting hepatic lipid accumulation. These results suggest that PRMT6 is critical in the control of lipid homeostasis by regulation of LXR alpha-mediated lipogenesis in the liver.

Keywords:  LXR; Lipogenesis; Liver; PRMT6

DOI:  https://doi.org/10.1016/j.metabol.2024.155938
Nat Metab. 2024 May;6(5): 847-860

Hippo-YAP/TAZ signalling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass.

Sungwoo Choi, Ju-Gyeong Kang, Yen T H Tran, Sun-Hye Jeong, Kun-Young Park, Hyemi Shin, Young Hoon Kim, Myungsun Park, Hahn Nahmgoong, Taejun Seol, Haeyon Jeon, Yeongmin Kim, Sanghee Park, Hee-Joo Kim, Min-Seob Kim, Xiaoxu Li, Maroun Bou Sleiman, Eries Lee, Jinhyuk Choi, David Eisenbarth, Sang Heon Lee, Suhyeon Cho, David D Moore, Johan Auwerx, Il-Young Kim, Jae Bum Kim, Jong-Eun Park, Dae-Sik Lim, Jae Myoung Suh.

Adipose tissues serve as an energy reservoir and endocrine organ, yet the mechanisms that coordinate these functions remain elusive. Here, we show that the transcriptional coregulators, YAP and TAZ, uncouple fat mass from leptin levels and regulate adipocyte plasticity to maintain metabolic homeostasis. Activating YAP/TAZ signalling in adipocytes by deletion of the upstream regulators Lats1 and Lats2 results in a profound reduction in fat mass by converting mature adipocytes into delipidated progenitor-like cells, but does not cause lipodystrophy-related metabolic dysfunction, due to a paradoxical increase in circulating leptin levels. Mechanistically, we demonstrate that YAP/TAZ-TEAD signalling upregulates leptin expression by directly binding to an upstream enhancer site of the leptin gene. We further show that YAP/TAZ activity is associated with, and functionally required for, leptin regulation during fasting and refeeding. These results suggest that adipocyte Hippo-YAP/TAZ signalling constitutes a nexus for coordinating adipose tissue lipid storage capacity and systemic energy balance through the regulation of adipocyte plasticity and leptin gene transcription.

DOI: https://doi.org/10.1038/s42255-024-01045-4
Mol Metab. 2024 May 28. pii: S2212-8778(24)00093-0. [Epub ahead of print] 101962

Inhibition of hepatic p63 ameliorates steatohepatitis with fibrosis in mice.

Marcos F Fondevila, Eva Novoa, Uxia Fernandez, Valentina Dorta, Tamara Parracho, Henriette Kreimeyer, Maria Garcia-Vence, Maria P Chantada-Vazquez, Susana B Bravo, Begoña Porteiro, Alba Cabaleiro, Mijra Koning, Ana Senra, Yara Souto, Joanne Verheij, Diana Guallar, Miguel Fidalgo, Abraham S Meijnikman, Natalia da Silva Lima, Carlos Dieguez, Maria J Gonzalez-Rellan, Ruben Nogueiras.

   OBJECTIVE: p63 is a transcription factor involved in multiple biological functions. In the liver, the TAp63 isoform induces lipid accumulation in hepatocytes. However, the role of liver TAp63 in the progression of metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis is unknown.
METHODS: We evaluated the hepatic p63 levels in different mouse models of steatohepatitis with fibrosis induced by diet. Next, we used virogenetic approaches to manipulate the expression of TAp63 in adult mice under diet-induced steatohepatitis with fibrosis and characterized the disease condition. Finally, we performed proteomics analysis in mice with overexpression and knockdown of hepatic TAp63.
RESULTS: Levels of TAp63, but not of ΔN isoform, are increased in the liver of mice with diet-induced steatohepatitis with fibrosis. Both preventive and interventional strategies for the knockdown of hepatic TAp63 significantly ameliorated diet-induced steatohepatitis with fibrosis in mice fed a methionine- and choline- deficient diet (MCDD) and choline deficient and high fat diet (CDHFD). The overexpression of hepatic TAp63 in mice aggravated the liver condition in mice fed a CDHFD. Proteomic analysis in the liver of these mice revealed alteration in multiple proteins and pathways, such as oxidative phosphorylation, antioxidant activity, peroxisome function and LDL clearance.
CONCLUSIONS: These results indicate that liver TAp63 plays a critical role in the progression of diet-induced steatohepatitis with fibrosis, and its inhibition ameliorates the disease.

Keywords:  MASH; MASLD; NAFLD; NASH; TAp63; fibrosis; liver; metabolism; p63; steatosis

DOI:  https://doi.org/10.1016/j.molmet.2024.101962
Aging Cell. 2024 May 27. e14227

Early life interventions metformin and trodusquemine metabolically reprogram the developing mouse liver through transcriptomic alterations.

Sarah A Ashiqueali, Augusto Schneider, Xiang Zhu, Ewelina Juszczyk, Mishfak A M Mansoor, Yun Zhu, Yimin Fang, Bianka M Zanini, Driele N Garcia, Natalie Hayslip, David Medina, Samuel McFadden, Robert Stockwell, Rong Yuan, Andrzej Bartke, Michael Zasloff, Shadab Siddiqi, Michal M Masternak.

  Recent studies have demonstrated the remarkable potential of early life intervention strategies at influencing the course of postnatal development, thereby offering exciting possibilities for enhancing longevity and improving overall health. Metformin (MF), an FDA-approved medication for type II diabetes mellitus, has recently gained attention for its promising anti-aging properties, acting as a calorie restriction mimetic, and delaying precocious puberty. Additionally, trodusquemine (MSI-1436), an investigational drug, has been shown to combat obesity and metabolic disorders by inhibiting the enzyme protein tyrosine phosphatase 1b (Ptp1b), consequently reducing hepatic lipogenesis and counteracting insulin and leptin resistance. In this study, we aimed to further explore the effects of these compounds on young, developing mice to uncover biomolecular signatures that are central to liver metabolic processes. We found that MSI-1436 more potently alters mRNA and miRNA expression in the liver compared with MF, with bioinformatic analysis suggesting that cohorts of differentially expressed miRNAs inhibit the action of phosphoinositide 3-kinase (Pi3k), protein kinase B (Akt), and mammalian target of rapamycin (Mtor) to regulate the downstream processes of de novo lipogenesis, fatty acid oxidation, very-low-density lipoprotein transport, and cholesterol biosynthesis and efflux. In summary, our study demonstrates that administering these compounds during the postnatal window metabolically reprograms the liver through induction of potent epigenetic changes in the transcriptome, potentially forestalling the onset of age-related diseases and enhancing longevity. Future studies are necessary to determine the impacts on lifespan and overall quality of life.

Keywords:  development; early life interventions; juvenile mice; lifespan and healthspan; liver metabolism; metformin; microRNAs and mRNAs; postnatal window; trodusquemine (3‐N‐1(spermine)‐7, 24‐dihydroxy‐5‐cholestane 24‐sulfate)

DOI:  https://doi.org/10.1111/acel.14227
Atherosclerosis. 2024 May 12. pii: S0021-9150(24)00138-2. [Epub ahead of print] 117578

Liver-specific Lxr inhibition represses reverse cholesterol transport in cholesterol-fed mice.

Takafumi Nishida, Makoto Ayaori, Junko Arakawa, Yumiko Suenaga, Kazusa Shiotani, Harumi Uto-Kondo, Tomohiro Komatsu, Kazuhiro Nakaya, Yasuhiro Endo, Makoto Sasaki, Katsunori Ikewaki.

   BACKGROUND AND AIMS: High density lipoprotein (HDL) exerts an anti-atherosclerotic effect via reverse cholesterol transport (RCT). Several phases of RCT are transcriptionally controlled by Liver X receptors (Lxrs). Although macrophage Lxrs reportedly promote RCT, it is still uncertain whether hepatic Lxrs affect RCT in vivo.
METHODS: To inhibit Lxr-dependent pathways in mouse livers, we performed hepatic overexpression of sulfotransferase family cytosolic 2B member 1 (Sult2b1) using adenoviral vector (Ad-Sult2b1). Ad-Sult2b1 or the control virus was intravenously injected into wild type mice and Lxrα/β double knockout mice, under a normal or high-cholesterol diet. A macrophage RCT assay and an HDL kinetic study were performed.
RESULTS: Hepatic Sult2b1 overexpression resulted in reduced expression of Lxr-target genes - ATP-binding cassette transporter G5/G8, cholesterol 7α hydroxylase and Lxrα itself - respectively reducing or increasing cholesterol levels in HDL and apolipoprotein B-containing lipoproteins (apoB-L). A macrophage RCT assay revealed that Sult2b1 overexpression inhibited fecal excretion of macrophage-derived 3H-cholesterol only under a high-cholesterol diet. In an HDL kinetic study, Ad-Sult2b1 promoted catabolism/hepatic uptake of HDL-derived cholesterol, thereby reducing fecal excretion. Finally, in Lxrα/β double knockout mice, hepatic Sult2b1 overexpression increased apoB-L levels, but there were no differences in HDL levels or RCT compared to the control, indicating that Sult2b1-mediated effects on HDL/RCT and apoB-L were distinct: the former was Lxr-dependent, but not the latter.
CONCLUSIONS: Hepatic Lxr inhibition negatively regulates circulating HDL levels and RCT by reducing Lxr-target gene expression.

Keywords:  ATP-Binding cassette transporter G5/G8; Cholesterol 7α hydroxylase; HDL-Cholesterol; Sulfotransferase family cytosolic 2B member 1 (Sult2b1)

DOI:  https://doi.org/10.1016/j.atherosclerosis.2024.117578
Sci Signal. 2024 May 28. 17(838): eado6266

Hippo and PI5P4K signaling intersect to control the transcriptional activation of YAP.

Lavinia Palamiuc, Jared L Johnson, Zeinab Haratipour, Ryan M Loughran, Woong Jae Choi, Gurpreet K Arora, Vivian Tieu, Kyanh Ly, Alicia Llorente, Sophia Crabtree, Jenny C Y Wong, Archna Ravi, Thorsten Wiederhold, Rabi Murad, Raymond D Blind, Brooke M Emerling.

Phosphoinositides are essential signaling molecules. The PI5P4K family of phosphoinositide kinases and their substrates and products, PI5P and PI4,5P2, respectively, are emerging as intracellular metabolic and stress sensors. We performed an unbiased screen to investigate the signals that these kinases relay and the specific upstream regulators controlling this signaling node. We found that the core Hippo pathway kinases MST1/2 phosphorylated PI5P4Ks and inhibited their signaling in vitro and in cells. We further showed that PI5P4K activity regulated several Hippo- and YAP-related phenotypes, specifically decreasing the interaction between the key Hippo proteins MOB1 and LATS and stimulating the YAP-mediated genetic program governing epithelial-to-mesenchymal transition. Mechanistically, we showed that PI5P interacted with MOB1 and enhanced its interaction with LATS, thereby providing a signaling connection between the Hippo pathway and PI5P4Ks. These findings reveal how these two important evolutionarily conserved signaling pathways are integrated to regulate metazoan development and human disease.

DOI: https://doi.org/10.1126/scisignal.ado6266
Sci Adv. 2024 May 31. 10(22): eadk9681

HSDL2 links nutritional cues to bile acid and cholesterol homeostasis.

Nolwenn Samson, Cristina R Bosoi, Christian Roy, Laurie Turcotte, Laura Tribouillard, Mathilde Mouchiroud, Line Berthiaume, Jocelyn Trottier, Heitor C G Silva, Thomas Guerbette, Ana Belén Plata-Gómez, Aurèle Besse-Patin, Alicia Montoni, Nicolò Ilacqua, Jennifer Lamothe, Yemima R Citron, Yves Gélinas, Stéphane Gobeil, Roberto Zoncu, Alexandre Caron, Mathieu Morissette, Luca Pellegrini, Patrick J Rochette, Jennifer L Estall, Alejo Efeyan, Michael Shum, Étienne Audet-Walsh, Olivier Barbier, André Marette, Mathieu Laplante.

In response to energy and nutrient shortage, the liver triggers several catabolic processes to promote survival. Despite recent progress, the precise molecular mechanisms regulating the hepatic adaptation to fasting remain incompletely characterized. Here, we report the identification of hydroxysteroid dehydrogenase-like 2 (HSDL2) as a mitochondrial protein highly induced by fasting. We show that the activation of PGC1α-PPARα and the inhibition of the PI3K-mTORC1 axis stimulate HSDL2 expression in hepatocytes. We found that HSDL2 depletion decreases cholesterol conversion to bile acids (BAs) and impairs FXR activity. HSDL2 knockdown also reduces mitochondrial respiration, fatty acid oxidation, and TCA cycle activity. Bioinformatics analyses revealed that hepatic Hsdl2 expression positively associates with the postprandial excursion of various BA species in mice. We show that liver-specific HSDL2 depletion affects BA metabolism and decreases circulating cholesterol levels upon refeeding. Overall, our report identifies HSDL2 as a fasting-induced mitochondrial protein that links nutritional signals to BAs and cholesterol homeostasis.

DOI: https://doi.org/10.1126/sciadv.adk9681
Cell. 2024 May 21. pii: S0092-8674(24)00514-2. [Epub ahead of print]

Gut bacteria convert glucocorticoids into progestins in the presence of hydrogen gas.

Megan D McCurry, Gabriel D D'Agostino, Jasmine T Walsh, Jordan E Bisanz, Ines Zalosnik, Xueyang Dong, David J Morris, Joshua R Korzenik, Andrea G Edlow, Emily P Balskus, Peter J Turnbaugh, Jun R Huh, A Sloan Devlin.

  Recent studies suggest that human-associated bacteria interact with host-produced steroids, but the mechanisms and physiological impact of such interactions remain unclear. Here, we show that the human gut bacteria Gordonibacter pamelaeae and Eggerthella lenta convert abundant biliary corticoids into progestins through 21-dehydroxylation, thereby transforming a class of immuno- and metabo-regulatory steroids into a class of sex hormones and neurosteroids. Using comparative genomics, homologous expression, and heterologous expression, we identify a bacterial gene cluster that performs 21-dehydroxylation. We also uncover an unexpected role for hydrogen gas production by gut commensals in promoting 21-dehydroxylation, suggesting that hydrogen modulates secondary metabolism in the gut. Levels of certain bacterial progestins, including allopregnanolone, better known as brexanolone, an FDA-approved drug for postpartum depression, are substantially increased in feces from pregnant humans. Thus, bacterial conversion of corticoids into progestins may affect host physiology, particularly in the context of pregnancy and women's health.

Keywords:  21-dehydroxylation; Eggerthella lenta; hydrogen gas; neurosteroids

DOI:  https://doi.org/10.1016/j.cell.2024.05.005
Nat Aging. 2024 May 30.

SGLT2 inhibition eliminates senescent cells and alleviates pathological aging.

Goro Katsuumi, Ippei Shimizu, Masayoshi Suda, Yohko Yoshida, Takaaki Furihata, Yusuke Joki, Chieh-Lun Hsiao, Liang Jiaqi, Shinya Fujiki, Manabu Abe, Masataka Sugimoto, Tomoyoshi Soga, Tohru Minamino.

It has been reported that accumulation of senescent cells in various tissues contributes to pathological aging and that elimination of senescent cells (senolysis) improves age-associated pathologies. Here, we demonstrate that inhibition of sodium-glucose co-transporter 2 (SGLT2) enhances clearance of senescent cells, thereby ameliorating age-associated phenotypic changes. In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the senescence load in visceral adipose tissue and improved adipose tissue inflammation and metabolic dysfunction, but normalization of plasma glucose by insulin treatment had no effect on senescent cells. Canagliflozin extended the lifespan of mice with premature aging even when treatment was started in middle age. Metabolomic analyses revealed that short-term treatment with canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, enhancing immune-mediated clearance of senescent cells by downregulating expression of programmed cell death-ligand 1. These findings suggest that inhibition of SGLT2 has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells.

DOI: https://doi.org/10.1038/s43587-024-00642-y