Prevention of Postprandial Metabolic Stress in Humans: Role of Fruit- Derived Products

Abstract Background Histone lactylation, a metabolic stress-related histone modification, plays an important role in the regulation of gene expression during M1 macrophage polarization. However, the role of histone lactylation in tumorigenesis remains unclear. Results Here, we show histone lactylation is elevated in tumors and is associated with poor prognosis of ocular melanoma. Target correction of aberrant histone lactylation triggers therapeutic efficacy both in vitro and in vivo. Mechanistically, histone lactylation contributes to tumorigenesis by facilitating YTHDF2 expression. Moreover, YTHDF2 recognizes the m6A modified PER1 and TP53 mRNAs and promotes their degradation, which accelerates tumorigenesis of ocular melanoma. Conclusion We reveal the oncogenic role of histone lactylation, thereby providing novel therapeutic targets for ocular melanoma therapy. We also bridge histone modifications with RNA modifications, which provides novel understanding of epigenetic regulation in tumorigenesis.

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Induction of mitochondrial heat shock proteins and mitochondrial biogenesis in endothelial cells upon acute methylglyoxal stress: Evidence for hormetic autofeedback

10.1101/2021.11.30.470545 ◽

2021 ◽

Author(s):

Ruben Bulkescher ◽

Thomas Fleming ◽

Claus Rodemer ◽

Rebekka Medert ◽

Marc Freichel ◽

...

Keyword(s):

Endothelial Cells ◽

Heat Shock ◽

Heat Shock Proteins ◽

Mitochondrial Biogenesis ◽

Metabolic Flux ◽

Metabolic Stress ◽

Oxidative Capacity ◽

Mitochondrial Proteins ◽

Shock Proteins

Increased metabolic flux produces potentially harmful side-products, such as reactive dicarbonyl and oxygen species. The reactive dicarbonly methylglyoxal (MG) can impair oxidative capacity, which is downregulated in type 2 diabetes. Heat shock proteins (HSPs) of subfamily A (Hsp70s) promote ATP-dependent processing of damaged proteins during MG exposure which also involve mitochondrial proteins. Since the protection of mitochondrial proteins could promote higher production of reactive metabolites due to increased substrate flux, tight regulation of HspA-mediated protein handling is important. We hypothesized that stress-inducible HspAs (HspA1A/HspA1B) are pivotal for maintaining mitochondrial biogenesis during acute MG-stress. To analyze the role of stress-inducible HspA1A/HspA1B for maintenance of mitochondrial homeostasis during acute MG exposure, we knocked out HSPA1A/HSPA1B in mouse endothelial cells. HSPA1A/HSPA1B KO cells showed upregulation of the mitochondrial chaperones HspA9 (mitochondrial Hsp70/mortalin) and HspD1 (Hsp60) as well as induction of mitochondrial biogenesis upon MG exposure. Increased mitochondrial biogenesis was reflected by elevated mitochondrial branching, total count and area as well as by upregulation of mitochondrial proteins and corresponding transcription factors. Our findings suggest that mitochondrial HspA9 and HspD1 promote mitochondrial biogenesis during acute MG stress, which is counterregulated by HspA1A/HspA1B to prevent mitochondrial overstimulation and to maintain balanced oxidative capacity under metabolic stress conditions. These data support an important role of HSPs in MG-induced hormesis.

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Abstract 88: A Crucial Role of BAG3 in Preventing Dilated Cardiomyopathy

Circulation Research ◽

10.1161/res.121.suppl_1.88 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Xi Fang ◽

Julius Bogomolovas ◽

Wei Zhang ◽

Tongbin Wu ◽

Canzhao Liu ◽

...

Keyword(s):

Heart Failure ◽

Dilated Cardiomyopathy ◽

Protein Quality ◽

Contractile Function ◽

Metabolic Stress ◽

Insoluble Fraction ◽

Therapeutic Benefit ◽

Loss Of Function ◽

Specific Subset

Defective protein quality control (PQC) systems are implicated in multiple diseases, with molecular chaperones/co-chaperones being critical to PQC. Cardiomyocytes are constantly challenged by mechanical and metabolic stress, placing great demand on the PQC system. Mutations and downregulation of the co-chaperone protein B cl-2- a ssociated athano g ene 3 (BAG3) are associated with cardiac myopathy and heart failure, and a BAG3 E455K mutation leads to Dilated cardiomyopathy (DCM). However, the role of BAG3 in the heart and mechanisms by which the E455K mutation lead to DCM remained obscure. Here, we found that cardiac-specific BAG3 knockout (CKO) and cardiac-specific E455K BAG3 knockin mice developed DCM. Comparable phenotypes in the two mutants demonstrated that the E455K mutation resulted in loss-of-function, and experiments revealed that the E455K mutation disrupted interaction between BAG3 and HSP70. In both mutants, decreased levels of small heat shock proteins (sHSPs) were observed, and a specific subset of proteins required for metabolic and contractile function of cardiomyocytes was enriched in the insoluble fraction. Together, these observations suggested that interaction between BAG3 and HSP70 was essential for BAG3 to stabilize sHSPs and maintain cardiomyocyte protein homeostasis. Our results provide new insight into the pathogenesis of heart failure caused by defects in BAG3 pathways, suggesting that increasing protein levels of BAG3 may be of therapeutic benefit in heart failure.

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Abstract 450: Monocytic Glutaredoxin 1 Protects Mice Against Obesity, Hyperglycemia and Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.450 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Kevin Downs ◽

Sina Tavakoli ◽

John D Short ◽

Huynh N Nguyen ◽

Reto Asmis

Keyword(s):

High Fat Diet ◽

Statistical Significance ◽

Gene Array ◽

Metabolic Stress ◽

Wild Type ◽

Adipose Tissues ◽

Atherosclerotic Lesions ◽

Monocyte Chemotaxis

Overexpression of glutaredoxin 1 (Grx1) protects monocytes from metabolic stress-induced priming, i.e. dysregulation and hypersensitization to chemokines (Ullevig et al. ATVB 2012). To address the role of monocytic Grx1 in mice and in the development of atherogenesis and obesity, we transplanted bone marrow (BM) from either wild-type (WT) or Grx1 -/- donor mice into atherosclerosis-prone LDLR -/- mice and fed these mice a high-fat diet (HFD) for up to 20 weeks. Grx1 Leuko -/- mice showed accelerated weight gain after 9 weeks followed by early onset of hyperglycemia. After 6 weeks on HFD, atherosclerotic lesions were slightly larger in Grx1 Leuko -/- mice than in WT mice, but the differences did not reach statistical significance. However, after 20 weeks, Grx1 Leuko -/- mice showed 36% larger lesions than WT-BM recipients, and monocyte chemotaxis in vivo was increased 1.6-fold. Furthermore, compared to WT-BM recipients, adipose tissues and livers of Grx1 Leuko -/- mice also showed increased macrophage content and elevated tissue inflammation as determined by IHC and qRT-PCR-based gene array. Adipose tissue in particular, showed significant increases in the expression of proinflammatory genes in addition to an increased abundance of proinflammatory “crown-like” structures. In contrast, genes associated with inflammation resolving macrophages were significantly suppressed. Macrophages isolated from Grx1 -/- mice and stimulated with INFγ+TNFα also showed increased expression of pro-inflammatory M1-associated genes, whereas M2-associated genes were suppressed in Grx-1 -/- macrophages activated with IL-4. Furthermore, macrophages from Grx1 -/- mice exposed to metabolic stress also display increased protein S -glutathionylation, enhanced hypersensitization to chemokine, and impaired autophagy compared to macrophages from wild-type mice. Taken together, our data show that loss of monocytic Grx1 worsens monocyte priming in response to HFD-induced metabolic stress and accelerates the infiltration of dysfunctional monocyte-derived macrophages into tissues, such as aorta, liver and adipose tissues. We conclude that monocytic Grx1 is critical for maintaining metabolic homeostasis in mice and protects mice against obesity and atherogenesis.

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The Intricate Role of p53 in Adipocyte Differentiation and Function

Cells ◽

10.3390/cells9122621 ◽

2020 ◽

Vol 9 (12) ◽

pp. 2621

Author(s):

Yun Kyung Lee ◽

Yu Seong Chung ◽

Ji Hye Lee ◽

Jin Mi Chun ◽

Jun Hong Park

Keyword(s):

Adipocyte Differentiation ◽

Metabolic Diseases ◽

Metabolic Stress ◽

Health Concern ◽

Metabolic Dysfunction ◽

Direct Role ◽

Proliferation And Apoptosis ◽

Response To Stress ◽

And Function

For more than three decades, numerous studies have demonstrated the function of p53 in cell cycle, cellular senescence, autophagy, apoptosis, and metabolism. Among diverse functions, the essential role of p53 is to maintain cellular homeostatic response to stress by regulating proliferation and apoptosis. Recently, adipocytes have been studied with increasing intensity owing to the increased prevalence of metabolic diseases posing a serious public health concern and because metabolic dysfunction can directly induce tumorigenesis. The prevalence of metabolic diseases has steadily increased worldwide, and a growing interest in these diseases has led to the focus on the role of p53 in metabolism and adipocyte differentiation with or without metabolic stress. However, our collective understanding of the direct role of p53 in adipocyte differentiation and function remains insufficient. Therefore, this review focuses on the newly discovered roles of p53 in adipocyte differentiation and function.

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Deubiquitinating enzyme USP30 maintains basal peroxisome abundance by regulating pexophagy

The Journal of Cell Biology ◽

10.1083/jcb.201804172 ◽

2019 ◽

Vol 218 (3) ◽

pp. 798-807 ◽

Cited By ~ 16

Author(s):

Victoria Riccio ◽

Nicholas Demers ◽

Rong Hua ◽

Miluska Vissa ◽

Derrick T. Cheng ◽

...

Keyword(s):

Amino Acid ◽

Ubiquitin Ligase ◽

Cell Function ◽

E3 Ubiquitin Ligase ◽

Metabolic Stress ◽

Amino Acid Starvation ◽

Deubiquitinating Enzyme ◽

Potential Therapeutic Target ◽

Autophagic Degradation

The regulation of organelle abundance is critical for cell function and survival; however, the mechanisms responsible are not fully understood. In this study, we characterize a role of the deubiquitinating enzyme USP30 in peroxisome maintenance. Peroxisomes are highly dynamic, changing in abundance in response to metabolic stress. In our recent study identifying the role of USP30 in mitophagy, we observed USP30 to be localized to punctate structures resembling peroxisomes. We report here that USP30, best known as a mitophagy regulator, is also necessary for regulating pexophagy, the selective autophagic degradation of peroxisomes. We find that overexpressing USP30 prevents pexophagy during amino acid starvation, and its depletion results in pexophagy induction under basal conditions. We demonstrate that USP30 prevents pexophagy by counteracting the action of the peroxisomal E3 ubiquitin ligase PEX2. Finally, we show that USP30 can rescue the peroxisome loss observed in some disease-causing peroxisome mutations, pointing to a potential therapeutic target.

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The Role of ZNF143 in Breast Cancer Cell Survival Through the NAD(P)H Quinone Dehydrogenase 1–p53–Beclin1 Axis Under Metabolic Stress

Cells ◽

10.3390/cells8040296 ◽

2019 ◽

Vol 8 (4) ◽

pp. 296 ◽

Cited By ~ 4

Author(s):

A Paek ◽

Ji Mun ◽

Mun Jo ◽

Hyosun Choi ◽

Yun Lee ◽

...

Keyword(s):

Breast Cancer ◽

Cell Survival ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Zinc Finger Protein ◽

Metabolic Stress ◽

Cancer Cell Survival ◽

Autophagic Process ◽

Low Expression

Autophagy is a cellular process that disrupts and uses unnecessary or malfunctioning components for cellular homeostasis. Evidence has shown a role for autophagy in tumor cell survival, but the molecular determinants that define sensitivity against autophagic regulation in cancers are not clear. Importantly, we found that breast cancer cells with low expression levels of a zinc-finger protein, ZNF143 (MCF7 sh-ZNF143), showed better survival than control cells (MCF7 sh-Control) under starvation, which was compromised with chloroquine, an autophagy inhibitor. In addition, there were more autophagic vesicles in MCF7 sh-ZNF143 cells than in MCF7 sh-Control cells, and proteins related with the autophagic process, such as Beclin1, p62, and ATGs, were altered in cells with less ZNF143. ZNF143 knockdown affected the stability of p53, which showed a dependence on MG132, a proteasome inhibitor. Data from proteome profiling in breast cancer cells with less ZNF143 suggest a role of NAD(P)H quinone dehydrogenase 1(NQO1) for p53 stability. Taken together, we showed that a subset of breast cancer cells with low expression of ZNF143 might exhibit better survival via an autophagic process by regulating the p53–Beclin1 axis, corroborating the necessity of blocking autophagy for the best therapy.

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HSF1 Regulates Mevalonate and Cholesterol Biosynthesis Pathways

Cancers ◽

10.3390/cancers11091363 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1363 ◽

Cited By ~ 2

Author(s):

Hyeji Kang ◽

Taerim Oh ◽

Young Yil Bahk ◽

Geon-Hee Kim ◽

Sang-Yeon Kan ◽

...

Keyword(s):

Cholesterol Biosynthesis ◽

Metabolic Stress ◽

Mapk Signaling ◽

Heat Shock Factor 1 ◽

Antiproliferative Effects ◽

Proteotoxic Stress ◽

Cholesterol Biosynthesis Pathway ◽

Increased Activity ◽

Essential Transcription Factor

Heat shock factor 1 (HSF1) is an essential transcription factor in cellular adaptation to various stresses such as heat, proteotoxic stress, metabolic stress, reactive oxygen species, and heavy metals. HSF1 promotes cancer development and progression, and increased HSF1 levels are frequently observed in multiple types of cancers. Increased activity in the mevalonate and cholesterol biosynthesis pathways, which are very important for cancer growth and progression, is observed in various cancers. However, the functional role of HSF1 in the mevalonate and cholesterol biosynthesis pathways has not yet been investigated. Here, we demonstrated that the activation of RAS-MAPK signaling through the overexpression of H-RasV12 increased HSF1 expression and the cholesterol biosynthesis pathway. In addition, the activation of HSF1 was also found to increase cholesterol biosynthesis. Inversely, the suppression of HSF1 by the pharmacological inhibitor KRIBB11 and short-hairpin RNA (shRNA) reversed H-RasV12-induced cholesterol biosynthesis. From the standpoint of therapeutic applications for hepatocellular carcinoma (HCC) treatment, HSF1 inhibition was shown to sensitize the antiproliferative effects of simvastatin in HCC cells. Overall, our findings demonstrate that HSF1 is a potential target for statin-based HCC treatment.

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