CELLULAR AND MOLECULAR LIFE SCIENCES
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2023
·Vol. 80
·期 3
·1-16
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IF 8
Li Xiaoxue,Zhang Yumeng,Chang Jianghao,Zhang Chenglin,Li Lin,Dai Yifan,Yang Haiyuan,Wang Ying
Previous studies have shown that mfat-1 transgenic mice have protective effects against some central nervous system (CNS) disorders, owing to the high docosahexaenoic acid (DHA) content enriched in their brains. However, whether this protective effect is connected to the blood – brain barrier (BBB) remains unclear. This study aims to investigate the mechanisms of the protective effect against hypoxic-ischemic brain damage (HIBD) of mfat-1 transgenic mice. mfat-1 mice not only demonstrated a significant amelioration of neurological dysfunction and neuronal damage but also partly maintained the physiological permeability of the BBB after HIBD. We initially showed this was associated with elevated major facilitator superfamily domain-containing 2a (Mfsd2a) expression on the BBB, resulting from more lysophosphatidylcholine (LPC)-DHA entering the brain. Wild-type (WT) mice showed a similar Mfsd2a expression trend after long-term feeding with an LPC-DHA-rich diet. Knockdown of Mfsd2a by siRNA intra-cerebroventricular (ICV) injection neutralized the protective effect against HIBD-induced BBB disruption in mfat-1 mice, further validating the protective function of Mfsd2a on BBB. HIBD-induced BBB high permeability was attenuated by Mfsd2a, primarily through a transcellular pathway to decrease caveolae-like vesicle-mediated transcytosis. Taken together, these findings not only reveal that mfat-1 transgenic mice have higher expression of Mfsd2a on the BBB, which partly sustains BBB permeability via vesicular transcytosis to alleviate the severity of HIBD, but also suggest that dietary intake of LPC-DHA may upregulate Mfsd2a expression as a novel therapeutic strategy for BBB dysfunction and survival in HIBD patients.
研究领域:
神经科学
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药理学
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分子生物学
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转化医学
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DOI
PubMed
高影响因子
EXPERIMENTAL PHYSIOLOGY
·
2021
·Vol. 106
·期 4
·983-993
·
IF 2.969
Changfeng Shan,Ronghua Wang,Shuai Wang,Zongmeng Zhang,Chaofeng Xing,Wenbin Feng,Zhenggang Zhao,Sujin Zhou,Allan Zijian Zhao,Yunping Mu,Fanghong Li
New Findings What is the central question of this study? What is the protective benefit of n −3 polyunsaturated fatty acids (PUFAs) on liver fibrosis and what are the relevant signalling pathways in a transgenic mouse model overexpressing the mfat-1 enzyme? What is the main finding and its importance? n −3 PUFA elevation strongly prevented carbon tetrachloride (CCl 4 )-induced hepatic damage and inhibited the activation of hepatic stellate cells. n −3 PUFAs suppressed CCl 4 -induced activation of mTOR, elevated Bcl-2 expression, and reduced Bax level, suggesting that n −3 PUFAs can render strong protective effects against liver fibrosis and point to the potential of mfat-1 gene therapy as a treatment modality. Liver fibrosis is a reversible wound healing response with excessive accumulation of extracellular matrix proteins. It is a globally prevalent disease with ultimately severe pathological consequences. However, very few current clinical therapeutic options are available. Nutritional addition of n −3 polyunsaturated fatty acids (PUFAs) can delay and lessen the development of liver fibrosis. Herein, this study examined the protective benefit of n −3 PUFAs on liver fibrosis and the relevant signalling pathways using a transgenic mouse model overexpressing the mfat-1 enzyme that converts n −6 to n −3 PUFAs. Male C57BL/6 wild-type and mfat-1 transgenic mice were administered carbon tetrachloride (CCl 4 ) or control corn oil by intraperitoneal injection. Blood alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were subsequently measured. CCl 4 -induced hepatic damage and fibrosis were assessed using haematoxylin–eosin and Masson's trichrome staining. Western blot assays were used to detect and quantify fibrosis-related proteins and mechanistic target of rapamycin (mTOR) and B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) signalling components. The direct effect of docosahexaenoic acid (DHA) on primary hepatic stellate cells (HSCs) was also investigated in a co-culture experiment. n −3 PUFAs, as a result of mfat-1 activity, had a strong protective effect on liver fibrosis. The elevation of ALT and AST induced by CCl 4 was significantly lessened in the mfat-1 mice. Histological determination revealed the protective effects of n −3 PUFAs on liver inflammation and collagen deposition. Co-incubation with DHA reduced the expression of profibrogenic factors in the primary HSCs. Moreover, mfat-1 transgenic mice showed significant reduction of proteins that are involved in mTOR and Bcl-2/Bax signalling pathways. Collectively, these results suggest that n −3 PUFA elevation strongly prevents CCl 4 -induced hepatic damage by directly inhibiting the activation of HSCs and regulating the basal activity of the mTOR and Bcl-2/Bax signalling pathways. Gene therapy applying mfat-1 and elevating n −3 PUFAs represents a promising treatment strategy to prevent liver fibrosis.
研究领域:
肝病学
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分子生物学
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药理学
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营养学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2023
·
IF 5.8
Chaofeng Xing,Minyi Tang,Jianqin Yang,Shuai Wang,Qihua Xu,Wenbin Feng,Yunping Mu,Fanghong Li,Allan Zijian Zhao
Type 1 diabetes mellitus (T1DM) is characterized by life-threatening absolute insulin deficiency . Although ω-3 polyunsaturated fatty acids (PUFAs) displayed significant anti-hyperglycemic activity, the insulinotropic effects of their metabolites remain unknown. In this study, we took advantage of a transgenic model , mfat-1, that overexpresses an ω-3 desaturase and can convert ω-6 PUFAs to ω-3 PUFAs. Eicosapentaenoic acid (EPA) was sharply elevated in the pancreatic tissues of mfat-1 transgenic mice compared with wild-type (WT) mice. In contrast to the WT mice, the mfat-1 transgenics did not develop overt diabetes and still maintained normal blood glucose levels and insulin secretion following streptozotocin-treatment. Furthermore, under the condition of pancreatic β-cell damage, co-incubation of the metabolites of EPA produced from the CYP 450 pathway with isolated islets promoted the overexpression of insulin as well as β-cell specific markers, pdx1 and Nkx6.1 in pancreatic α-cells. Addition of EPA metabolites to the cultured glucagon-positive α-cell lines, a series of pancreatic β-cell markers were also found significantly elevated. Combined together, these results demonstrated the effects of ω-3 PUFAs and their metabolites on the trans-differentiation from α-cells to β-cells and its potential usage in the intervention of T1DM.
研究领域:
内分泌学
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糖尿病研究
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
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