The mechanism and role of intracellular α-ketoglutarate reduction in hepatic stellate cell activation

Zhao, Jianjian; Jiang, Yueping; Sun, Xue‐Guo; Liu, Xi-Shuang; Liu, Fuguo; Song, Mengxiong; Zhang, Lingyun

doi:10.1042/bsr20193385

Cited by 4 publications

(8 citation statements)

References 37 publications

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“…Decreased IDH2 expression limits alpha-ketoglutarate production during HSCs activation, which in turn promotes HSCs activation via a TGF-β1-independent pathway. Therefore, IDH2 and α-ketoglutarate might be potential novel targets to LF therapy [45] . Nestin, a type VI intermediate filament protein, was first identified in neural stem cells (NSCs) and is closely related to the self-renewal of NSCs.…”

Section: Other Roles With Smad Signaling Pathwaymentioning

confidence: 99%

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

Zheng

Yang

Luo

et al. 2022

Preprint

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Liver fibrosis (LF) is a trauma repair process carried out by the liver in response to various acute and chronic liver injuries, featured by excessive proliferation as well as abnormal dismissal of extracellular matrix as the main pathological features, and its continuous development will deteriorate into cirrhosis, liver cancer as well as other illnesses. The occurrence of LF is closely related to Hepatic stellate cells (HSCs) stimulation, and intervention in HSCs proliferation is expected to reverse LF. Plant-based small molecule drugs have anti-LF effects, and their mechanisms of action are related to anti-inflammation, anti-oxidative stress, as well as inhibition of abnormal accumulation of extracellular matrix. Consequently, new agents for HSCs will be required to furnish a possible curative response. Small-molecule natural products might be attractive for LF therapy. That is because they not only have the effect against HSCs, but also have excellent qualities such as low toxic side effects and easy availability from the perspective of safety and cost. In this review, we provide an updated review of the signal transduction pathways involved in HSCs and small-molecule natural products targeting HSCs reported in the past 3 years at home and abroad, with the aim of providing new ideas for the development of plant-based small molecule drugs targeting HSCs to reverse LF.

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Section: Other Roles With Smad Signaling Pathwaymentioning

confidence: 99%

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

Zheng

Yang

Luo

et al. 2022

Preprint

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“…He et al found that by interfering with the intestinal flora, AKG can promote the differentiation of intestinal cells and slow down the development of colorectal cancer by inhibiting the WNT pathway [12]. In addition, AKG is considered a potential new target for the prevention and treatment of liver fibrosis [13]. Additionally, Tatara et al found that adding AKG to the diet of piglets before and after weaning can effectively promote the formation of bone tissue [14].…”

Section: Introductionmentioning

confidence: 99%

“…As metabolites serve as direct signatures of biochemical activity [20], metabolomics analysis has been used to systematically elucidate the molecular mechanisms of nutritional supplements [13,21]. Meanwhile, 1 H nuclear magnetic resonance (NMR) has been identified as a robust technique for metabonomic applications due to its prominent advantages [22,23].…”

Section: Introductionmentioning

confidence: 99%

NMR-Based Metabolic Profiling of the Effects of α-Ketoglutarate Supplementation on Energy-Deficient C2C12 Myotubes

Zhang

Huang

et al. 2023

Molecules

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Skeletal muscle is closely linked to energy metabolism, but it is inevitably deprived of energy. Cellular differentiation is an essential and energy-demanding process in skeletal muscle development. Much attention has been paid to identifying beneficial factors that promote skeletal muscle satellite cell differentiation and further understanding the underlying regulatory mechanisms. As a critical metabolic substrate or regulator, α-ketoglutarate (AKG) has been recognized as a potential nutritional supplement or therapeutic target for skeletal muscle. We have previously found beneficial effects of AKG supplementation on the proliferation of C2C12 myoblasts cultured under both normal and energy-deficient conditions and have further elucidated the underlying metabolic mechanisms. However, it remains unclear what role AKG plays in myotube formation in different energy states. In the present study, we investigated the effects of AKG supplementation on the differentiation of C2C12 myoblasts cultured in normal medium (Nor myotubes) and low glucose medium (Low myotubes) and performed NMR-based metabonomic profiling to address AKG-induced metabolic changes in both Nor and Low myotubes. Significantly, AKG supplementation promoted myotube formation and induced metabolic remodeling in myotubes under normal medium and low glucose medium, including improved energy metabolism and enhanced antioxidant capacity. Specifically, AKG mainly altered amino acid metabolism and antioxidant metabolism and upregulated glycine levels and antioxidase expression. Our results are typical for the mechanistic understanding of the effects of AKG supplementation on myotube formation in the two energy states. This study may be beneficial for further exploring the applications of AKG supplementation in sports, exercise, and therapy.

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“…Various nutritional supplements have been employed to promote skeletal muscle hypertrophy and enhance sports performance [ 1 ]. As the intersection of the organic carbon and nitrogen metabolism and simultaneously a critical intermediate in the TCA cycle, α-Ketoglutarate (AKG) has shown pleiotropic effects for improving muscle performance in clinical and animal experiments [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. For example, AKG can reduce intestinal mucosal damage [ 8 ] and inflammation [ 9 ], attenuate the development of colorectal cancer [ 4 ] and liver fibrosis [ 5 ], promote growth [ 6 ], and reduce morbidity and delay aging [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…As the intersection of the organic carbon and nitrogen metabolism and simultaneously a critical intermediate in the TCA cycle, α-Ketoglutarate (AKG) has shown pleiotropic effects for improving muscle performance in clinical and animal experiments [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. For example, AKG can reduce intestinal mucosal damage [ 8 ] and inflammation [ 9 ], attenuate the development of colorectal cancer [ 4 ] and liver fibrosis [ 5 ], promote growth [ 6 ], and reduce morbidity and delay aging [ 7 ]. Previous works have demonstrated that AKG supplementation can alleviate muscle loss by parenteral administration in a trauma model of patients undergoing total hip replacement [ 2 ], and promote muscle hypertrophy and protein synthesis through Akt/mTOR signaling pathways [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

NMR-Based Metabolomic Analysis for the Effects of α-Ketoglutarate Supplementation on C2C12 Myoblasts in Different Energy States

Gao

et al. 2021

Molecules

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α-Ketoglutarate (AKG) is attracting much attention from researchers owing to its beneficial effects on anti-aging and cancer suppression, and, more recently, in nutritional supplements. Given that glucose is the main source of energy to maintain normal physiological functions of skeletal muscle, the effects of AKG supplementation for improving muscle performance are closely related to the glucose level in skeletal muscle. The differences of AKG-induced effects in skeletal muscle between two states of normal energy and energy deficiency are unclear. Furthermore, AKG-induced metabolic changes in skeletal muscles in different energy states also remain elusive. Here, we assessed the effects of AKG supplementation on mouse C2C12 myoblast cells cultured both in normal medium (Nor cells) and in low-glucose medium (Low cells), which were used to mimic two states of normal energy and energy deficiency, respectively. We further performed NMR-based metabolomic analysis to address AKG-induced metabolic changes in Nor and Low cells. AKG supplementation significantly promoted the proliferation and differentiation of cells in the two energy states through glutamine metabolism, oxidative stress, and energy metabolism. Under normal culture conditions, AKG up-regulated the intracellular glutamine level, changed the cellular energy status, and maintained the antioxidant capacity of cells. Under low-glucose culture condition, AKG served as a metabolic substrate to reduce the glutamine-dependence of cells, remarkably enhanced the antioxidant capacity of cells and significantly elevated the intracellular ATP level, thereby ensuring the normal growth and metabolism of cells in the state of energy deficiency. Our results provide a mechanistic understanding of the effects of AKG supplements on myoblasts in both normal energy and energy deficiency states. This work may be beneficial to the exploitation of AKG applications in clinical treatments and nutritional supplementations.

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The mechanism and role of intracellular α-ketoglutarate reduction in hepatic stellate cell activation

Cited by 4 publications

References 37 publications

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

NMR-Based Metabolic Profiling of the Effects of α-Ketoglutarate Supplementation on Energy-Deficient C2C12 Myotubes

NMR-Based Metabolomic Analysis for the Effects of α-Ketoglutarate Supplementation on C2C12 Myoblasts in Different Energy States

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