ABSTRACT
In this editorial, we comment on an article by Liao et al published in the current issue of the World Journal of Diabetes. We focus on the clinical significance of tibial transverse transport (TTT) as an effective treatment for patients with diabetic foot ulcers (DFU). TTT has been associated with tissue regeneration, improved blood circulation, reduced amputation rates, and increased expression of early angiogenic factors. Mechanistically, TTT can influence macrophage polarization and growth factor upregulation. Despite this potential, the limitations and conflicting results of existing studies justify the need for further research into its optimal application and development. These clinical implications highlight the efficacy of TTT in recalcitrant DFU and provide lasting stimuli for tissue re-generation, and blood vessel and bone marrow improvement. Immunomodulation via systemic responses contributes to its therapeutic potential. Future studies should investigate the underlying molecular mechanisms to enhance our understanding and the efficacy of TTT. This manuscript emphasizes the potential of TTT in limb preservation and diabetic wound healing and suggests avenues for preventive measures against limb amputation in diabetes and peripheral artery disease. Here, we highlight the clinical significance of the TTT and its importance in healing DFU to promote the use of this technique in tissue regeneration.
ABSTRACT
Betaine-homocysteine S-methyltransferase (BHMT) is one of the most abundant proteins in the liver and regulates homocysteine metabolism. However, the molecular mechanisms underlying Bhmt transcription have not yet been elucidated. This study aimed to assess the molecular mechanisms underlying Bhmt transcription and the effect of BHMT deficiency on metabolic functions in the liver mediated by liver receptor homolog-1 (LRH-1). During fasting, both Bhmt and Lrh-1 expression increased in the liver of Lrh-1f/f mice; however, Bhmt expression was decreased in LRH-1 liver specific knockout mice. Promoter activity analysis confirmed that LRH-1 binds to a specific site in the Bhmt promoter region. LRH-1 deficiency was associated with elevated production of reactive oxygen species (ROS), lipid peroxidation, and mitochondrial stress in hepatocytes, contributing to hepatic triglyceride (TG) accumulation. In conclusion, this study suggests that the absence of an LRH-1-mediated decrease in Bhmt expression promotes TG accumulation by increasing ROS levels and inducing mitochondrial stress. Therefore, LRH-1 deficiency not only leads to excess ROS production and mitochondrial stress in hepatocytes, but also disrupts the methionine cycle. Understanding these regulatory pathways may pave the way for novel therapeutic interventions against metabolic disorders associated with hepatic lipid accumulation.
Subject(s)
Betaine-Homocysteine S-Methyltransferase , Hepatocytes , Liver , Methionine , Mice, Knockout , Reactive Oxygen Species , Receptors, Cytoplasmic and Nuclear , Triglycerides , Animals , Liver/metabolism , Mice , Reactive Oxygen Species/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Cytoplasmic and Nuclear/genetics , Betaine-Homocysteine S-Methyltransferase/metabolism , Betaine-Homocysteine S-Methyltransferase/genetics , Hepatocytes/metabolism , Methionine/metabolism , Triglycerides/metabolism , Promoter Regions, Genetic/genetics , Male , Mice, Inbred C57BL , Mitochondria/metabolism , Lipid PeroxidationABSTRACT
Sterol regulatory element-binding protein (SREBP)-1c is involved in cellular lipid homeostasis and cholesterol biosynthesis and is highly increased in nonalcoholic steatohepatitis (NASH). However, the molecular mechanism by which SREBP-1c regulates hepatic stellate cells (HSCs) activation in NASH animal models and patients have not been fully elucidated. In this study, we examined the role of SREBP-1c in NASH and the regulation of LCN2 gene expression. Wild-type and SREBP-1c knockout (1cKO) mice were fed a high-fat/high-sucrose diet, treated with carbon tetrachloride (CCl4), and subjected to lipocalin-2 (LCN2) overexpression. The role of LCN2 in NASH progression was assessed using mouse primary hepatocytes, Kupffer cells, and HSCs. LCN2 expression was examined in samples from normal patients and those with NASH. LCN2 gene expression and secretion increased in CCl4-induced liver fibrosis mice model, and SREBP-1c regulated LCN2 gene transcription. Moreover, treatment with holo-LCN2 stimulated intracellular iron accumulation and fibrosis-related gene expression in mouse primary HSCs, but these effects were not observed in 1cKO HSCs, indicating that SREBP-1c-induced LCN2 expression and secretion could stimulate HSCs activation through iron accumulation. Furthermore, LCN2 expression was strongly correlated with inflammation and fibrosis in patients with NASH. Our findings indicate that SREBP-1c regulates Lcn2 gene expression, contributing to diet-induced NASH. Reduced Lcn2 expression in 1cKO mice protects against NASH development. Therefore, the activation of Lcn2 by SREBP-1c establishes a new connection between iron and lipid metabolism, affecting inflammation and HSCs activation. These findings may lead to new therapeutic strategies for NASH.
Subject(s)
Iron , Lipocalin-2 , Liver Cirrhosis , Mice, Knockout , Non-alcoholic Fatty Liver Disease , Sterol Regulatory Element Binding Protein 1 , Animals , Humans , Male , Mice , Carbon Tetrachloride/pharmacology , Disease Models, Animal , Gene Expression Regulation , Hepatic Stellate Cells/metabolism , Hepatic Stellate Cells/pathology , Hepatocytes/metabolism , Hepatocytes/pathology , Iron/metabolism , Lipocalin-2/metabolism , Lipocalin-2/genetics , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Liver Cirrhosis/etiology , Liver Cirrhosis/genetics , Liver Cirrhosis/chemically induced , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/pathology , Non-alcoholic Fatty Liver Disease/genetics , Sterol Regulatory Element Binding Protein 1/metabolism , Sterol Regulatory Element Binding Protein 1/geneticsABSTRACT
Antiretroviral therapy-naive people living with HIV possess less fat than people without HIV. Previously, we found that HIV-1 transactivator of transcription (TAT) decreases fat in ob/ob mice. The TAT38 (a.a. 20-57) is important in the inhibition of adipogenesis and contains three functional domains: Cys-ZF domain (a.a. 20-35 TACTNCYCAKCCFQVC), core-domain (a.a. 36-46, FITKALGISYG), and protein transduction domain (PTD)(a.a. 47-57, RAKRRQRRR). Interestingly, the TAT38 region interacts with the Cyclin T1 of the P-TEFb complex, of which expression increases during adipogenesis. The X-ray crystallographic structure of the complex showed that the Cys-ZF and the core domain bind to the Cyclin T1 via hydrophobic interactions. To prepare TAT38 mimics with structural and functional similarities to TAT38, we replaced the core domain with a hydrophobic aliphatic amino acid (from carbon numbers 5 to 8). The TAT38 mimics with 6-hexanoic amino acid (TAT38 Ahx (C6)) and 7-heptanoic amino acid (TAT38 Ahp (C7)) inhibited adipogenesis of 3T3-L1 potently, reduced cellular triglyceride content, and decreased body weight of diet-induced obese (DIO) mice by 10.4-11 % in two weeks. The TAT38 and the TAT38 mimics potently repressed the adipogenic transcription factors genes, C/EBPα, PPARγ, and SREBP1. Also, they inhibit the phosphorylation of PPARγ. The TAT peptides may be promising candidates for development into a drug against obesity or diabetes.