PSTi8 with metformin ameliorates perimenopause induced steatohepatitis associated ER stress by regulating SIRT-1/SREBP-1c axis.
PSTi8 with metformin ameliorates perimenopause induced steatohepatitis associated ER stress by regulating SIRT-1/SREBP-1c axis.
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DOI：
10.1016/j.heliyon.2020.e05826
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发表时间：
2020-12
期刊：
影响因子：
4
通讯作者：
Gayen JR
中科院分区：
文献类型：
--
作者：
Singh P;Reza MI;Syed AA;Garg R;Husain A;Katekar R;Goand UK;Riyazuddin M;Gupta AP;Gayen JR
面临绝经的女性肝脏脂肪变性是大量果糖消耗的表现，并形成正反馈回路以发展内质网（ER）应激。先前的胰蛋白酶抑制剂肽-8（PSTi 8）和蛋氨酸（Met）组合以降低的剂量有效地改善了高果糖饮食（HFrD）喂养的糖尿病小鼠模型中的肝脏脂质积累。此外，SIRT-1在SREBP-1c的调节中起着至关重要的作用。因此，我们假设Met和PST 18的组合（治疗性较低剂量）可以通过在HFrD喂养的4-乙烯基环己烯二环氧化物（HVCD）诱导的围绝经期大鼠中激活SIRT-1并排除SREBP-1c来减轻与肝脂肪变性相关的ER应激。给HVCD大鼠喂食HFrD 12周，同时用Met、PSTi 8和组合治疗14天。通过发情周期、雌二醇水平和腹腔葡萄糖耐量试验确定模型的建立。测定血脂和肝功能。此外，mRNA和蛋白质的表达进行了检查。免疫荧光染色检测SIRT-1和SREBP-1c在HepG 2细胞中的分布。HVCD组显示胰岛素抵抗（IR）、脂肪生成和肝脏ER应激增强。联合治疗改善了HVCD大鼠的发情周期、雌二醇和血脂。Met和PSTi 8组合降低了高果糖诱导的胰岛素抵抗HepG 2细胞中的肝SREBP-1c并触发了SIRT-1表达;因此，组合治疗减弱了ER应激。简而言之，本研究促进了关于Met与PSTi 8在较低治疗剂量下的治疗作用的动力，以通过改造围绝经期大鼠中的SIRT-1/SREBP-1c轴来改善肝脏IR、脂肪变性和相关的ER应激。联合治疗（Met + PSTi 8）; PSTi 8; Metabolic;肝脂肪变性; ER应激; SIRT-1; SREBP-1c;围绝经期大鼠
Hepatic steatosis in women confronting menopause is the manifestation of substantial fructose consumption and forms a positive feedback loop to develop endoplasmic reticulum (ER) stress. Previously pancreastatin inhibitor peptide-8 (PSTi8) and Metformin (Met) combination effectively ameliorated hepatic lipid accumulation in high fructose diet (HFrD) fed diabetic mice models at reduced doses. Moreover, SIRT-1 plays a crucial role in the regulation of SREBP-1c. Hence we hypothesized that Met and PSTi8 in combination (at therapeutic lower doses) could mitigate hepatic steatosis linked ER stress by activating SIRT-1 and precluding SREBP-1c in HFrD fed 4-Vinylcyclohexenediepoxide (HVCD) induced perimenopausal rats. HVCD rats were fed HFrD for 12 weeks, accompanied by 14 days of treatment with Met, PSTi8, and combination. We confirmed model establishment by estrus cycle study, estradiol level, and intraperitoneal glucose tolerance test. Plasma lipid profile and liver function were determined. Also, mRNA and protein expressions were examined. Moreover, distribution of SIRT-1 and SREBP-1c was detected in HepG2 cells by immunofluorescence staining. HVCD group displayed augmented insulin resistance (IR), lipogenesis, and ER stress in the liver. Combination therapy improved the estrus cyclicity, estradiol, and lipid profile of HVCD rats. Met and PSTi8 combination reduced hepatic SREBP-1c and triggered SIRT-1 expression in high fructose-induced insulin-resistant HepG2 cells; consequently, combination therapy attenuated ER stress. Succinctly, present research promotes impetus concerning the remedial impact of Met with PSTi8 at lower therapeutic doses to ameliorate hepatic IR, steatosis, and associated ER stress by revamping the SIRT-1/SREBP-1c axis in perimenopausal rats. Combination therapy (Met + PSTi8); PSTi8; Metformin; Hepatic steatosis; ER stress; SIRT-1; SREBP-1c; Perimenopausal rat
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影响因子：
7.5
作者：
Gupta, Anand P.;Singh, Pragati;Gayen, Jiaur R.
通讯作者：
Gayen, Jiaur R.
影响因子：
56.9
作者：
Lee, Ann-Hwee;Scapa, Erez F.;Glimcher, Laurie H.
通讯作者：
Glimcher, Laurie H.
影响因子：
5.2
作者：
Cuyàs E;Verdura S;Llorach-Parés L;Fernández-Arroyo S;Joven J;Martin-Castillo B;Bosch-Barrera J;Brunet J;Nonell-Canals A;Sanchez-Martinez M;Menendez JA
通讯作者：
Menendez JA
人类脂肪肝病：旧问题和新见解。
DOI：
10.1126/science.1204265
发表时间：
2011-06-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cohen JC;Horton JD;Hobbs HH
通讯作者：
Hobbs HH
影响因子：
3.3
作者：
Kim, Do-Sung;Jeong, Seul-Ki;Chae, Han-Jung
通讯作者：
Chae, Han-Jung