Fatty acid metabolization and insulin regulation prevent liver injury from lipid accumulation in Himalayan marmots

Bao, Ziqiang; Cheng, Guo; Chen, Yi; Cheng, Li; Tao, Ling; Zhou, Shuailing; Qi, Dunwu; Xiang, Zuofu

doi:10.1016/j.celrep.2023.112718

Cited by 3 publications

(10 citation statements)

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“…Alternatively, the cellular membrane composition of hibernators may be intrinsically distinct from that of non-hibernators, or seasonally adapted to achieve cold resistance and maintain membrane fluidity under cold conditions, which could affect the structure of membrane proteins that are vital for maintaining cellular ion homeostasis ( Aloia and Raison, 1989 ; Giroud et al, 2013 ; Cheff et al, 2021 ). Further efforts to answer these questions in detail will be necessary in specific model hibernators such as Syrian hamsters, in which the causal relationship between genes and phenomena can be functionally addressed, in combination with candidate genes and candidate molecules accumulated through the latest bioinformatics, omics, and comparative approaches in various hibernators, including ground squirrels, marmots, dormice, chipmunks, bats, and bears ( Fedorov et al, 2014 ; Villanueva-Canas et al, 2014 ; Ferris and Gregg, 2019 ; Grabek et al, 2019 ; Jansen et al, 2019 ; Gillen et al, 2021 ; Chen and Mao, 2022 ; Bao et al, 2023 ; Christmas et al, 2023 ; Haugg et al, 2023 ; Heinis et al, 2023 ; Takamatsu et al, 2023 ; Thienel et al, 2023 ; Yang et al, 2023 ). Based on these studies, we will further clarify Q4 and its related question whether cold resistance associated with hibernation originates from a common ancestral trait or as a result of convergent evolution across distinct mammalian clades.…”

Section: Open Questions and Future Perspectivesmentioning

confidence: 99%

Cold resistance of mammalian hibernators ∼ a matter of ferroptosis?

Sone,

Yamaguchi

2024

Front. Physiol.

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Most mammals adapt thermal physiology around 37°C and large deviations from their range, as observed in severe hypothermia and hyperthermia, resulting in organ dysfunction and individual death. A prominent exception is mammalian hibernation. Mammalian hibernators resist the long-term duration of severe low body temperature that is lethal to non-hibernators, including humans and mice. This cold resistance is supported, at least in part, by intrinsic cellular properties, since primary or immortalized cells from several hibernator species can survive longer than those from non-hibernators when cultured at cold temperatures. Recent studies have suggested that cold-induced cell death fulfills the hallmarks of ferroptosis, a type of necrotic cell death that accompanies extensive lipid peroxidation by iron-ion-mediated reactions. In this review, we summarize the current knowledge of cold resistance of mammalian hibernators at the cellular and molecular levels to organ and systemic levels and discuss key pathways that confer cold resistance in mammals.

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Section: Open Questions and Future Perspectivesmentioning

confidence: 99%

Cold resistance of mammalian hibernators ∼ a matter of ferroptosis?

Sone,

Yamaguchi

2024

Front. Physiol.

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“…Hibernating species like the 13-lined ground squirrel, Daurian ground squirrel, greater horseshoe bat, and brown bear have undergone thorough studies concerning their gut microbiota [ 2 , 16 , 17 , 18 ]. Due to winter fasting, the host experiences a sharp reduction in degradable substrates available for gut microbiota, which can impact the variety and composition of the gut microbial community [ 19 ].…”

Section: Effects Of Hibernation On the Gut Microbes Of Mammalian Animalsmentioning

confidence: 99%

“…However, an overabundance of fat accumulation has the potential to result in liver impairment, manifesting as conditions like non-alcoholic fatty liver disease (NAFLD) [ 47 , 48 ]. Findings from Bao et al indicated that Himalayan marmots in the pre-hibernation active phase exhibit a preference for dietary options abundant in unsaturated fatty acids (UFAs) [ 2 ], and there was a notable positive correlation between the intake of unsaturated fatty acids and body weight [ 49 ]. This preference is potentially attributed to the absence of desaturase enzymes in mammals, which hinders the endogenous synthesis of UFAs.…”

Section: Effects Of Gut Microbiota On the Host During Hibernationmentioning

confidence: 99%

“…This preference is potentially attributed to the absence of desaturase enzymes in mammals, which hinders the endogenous synthesis of UFAs. UFAs are likely instrumental in facilitating the fat accumulation observed in Himalayan marmots [ 2 ]. Metagenomic analysis reveals a significant upregulation in the biosynthesis of UFAs within the Firmicutes CAG:110 .…”

Section: Effects Of Gut Microbiota On the Host During Hibernationmentioning

confidence: 99%

“…During hibernation, animals undergo adaptive changes such as reduced body temperature, slowed metabolism, and decreased heart rate [ 1 ]. The dietary composition of hibernating animals exhibits seasonal variations, with most of them increasing their food intake during the summer and the autumn to store fat, while fasting during hibernation [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

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The Research Progress on the Interaction between Mammalian Gut Microbiota and the Host’s Metabolism Homeostasis during Hibernation

Zhang,

Song,

Wang

et al. 2024

Metabolites

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Hibernating mammals confront seasonal and harsh environmental shifts, prompting a cycle of pre-hibernation feeding and subsequent winter fasting. These adaptive practices induce diverse physiological adjustments within the animal’s body. With the gut microbiota’s metabolic activity being heavily reliant on the host’s diet, this cycle’s primary impact is on this microbial community. When the structure and composition of the gut microbiota changes, corresponding alterations in the interactions occur between these microorganisms and their host. These successive adaptations significantly contribute to the host’s capacity to sustain relatively stable metabolic and immune functions in severe environmental conditions. A thorough investigation into the reciprocal interplay between the host and gut microbiota during hibernation-induced adaptive changes holds promise for unveiling new insights. Understanding the underlying mechanisms driving these interactions may potentially unlock innovative approaches to address extreme pathological conditions in humans.

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5-aminolevulinate and CHIL3/CHI3L1 treatment amid ischemia aids liver metabolism and reduces ischemia-reperfusion injury

Jin,

Guo,

Liu

et al. 2023

Theranostics

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Rationale: Liver resection and transplantation surgeries are accompanied by hepatic ischemia-reperfusion (HIR) injury that hampers the subsequent liver recovery. Given that the liver is the main organ for metabolism and detoxification, ischemia-reperfusion in essence bestows metabolic stress upon the liver and disrupts local metabolic and immune homeostasis. Most of the recent and current research works concerning HIR have been focusing on addressing HIR-induced hepatic injury and inflammation, instead of dealing with the metabolic reprogramming and restoration of redox homeostasis. As our previous work uncovers the importance of 5-aminolevulinate (5-ALA) synthesis during stress adaptation, here we evaluate the effects of supplementing 5-ALA to mitigate HIR injury. Methods: 5-ALA was supplemented into the mice or cultured cells during the ischemic or oxygen-glucose deprivation (OGD) phase. Following reperfusion or reoxygenation, cellular metabolism and energy homeostasis, mitochondrial production of reactive oxygen species (ROS) and transcriptomic changes were evaluated in HIR mouse models or cultured hepatocytes and macrophages. Liver injury, hepatocytic functional tests, and macrophagic M1/M2 polarization were assessed. Results: Dynamic changes in the expression of key enzymes in 5-ALA metabolism were first confirmed in donor and mouse liver samples following HIR. Supplemented 5-ALA modulated mouse hepatic lipid metabolism and reduced ATP production in macrophages following HIR, resulting in elevation of anti-inflammatory M2 polarization. Mechanistically, 5-ALA down-regulates macrophagic chemokine receptor CX3CR1 via the repression of RelA following OGD and reoxygenation (OGD/R). Cx3cr1 KO mice demonstrated milder liver injuries and more macrophage M2 polarization after HIR. M2 macrophage-secreted chitinase-like protein 3 (CHIL3; CHI3L1 in human) is an important HIR-induced effector downstream of CX3CR1 deficiency. Addition of CHIL3/CHI3L1 alone improved hepatocellular metabolism and reduced OGD/R-inflicted injuries in cultured mouse and human hepatocytes. Combined treatment with 5-ALA and CHIL3 during the ischemic phase facilitated lipid metabolism and ATP production in the mouse liver following HIR. Conclusion: Our results reveal that supplementing 5-ALA promotes macrophagic M2 polarization via downregulation of RelA and CX3CR1 in mice following HIR, while M2 macrophage-produced CHIL3/CHI3L1 also manifests beneficial effects to the recovery of hepatic metabolism. 5-ALA and CHIL3/CHI3L1 together mitigate HIR-induced mitochondrial dysfunction and hepatocellular injuries, which may be developed into safe and effective clinical treatments to attenuate HIR injuries.

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Fatty acid metabolization and insulin regulation prevent liver injury from lipid accumulation in Himalayan marmots

Cited by 3 publications

References 74 publications

Cold resistance of mammalian hibernators ∼ a matter of ferroptosis?

Cold resistance of mammalian hibernators ∼ a matter of ferroptosis?

The Research Progress on the Interaction between Mammalian Gut Microbiota and the Host’s Metabolism Homeostasis during Hibernation

5-aminolevulinate and CHIL3/CHI3L1 treatment amid ischemia aids liver metabolism and reduces ischemia-reperfusion injury

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