BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
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2025
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IF 3.3
Qinghua Fu,Peng Wang,Weilin Li,Zhenhua Cai,Shiji Zhao,Weidong Ling,Mingxun Li,Xiaochuan Tang,Ziyi Song
Obesity poses a significant risk for metabolic disorders, such as insulin resistance and metabolic-associated fatty liver disease (MAFLD), yet effective treatments remain limited. Cell Death-Inducing DNA Fragmentation Factor-α-Like Effector C (CIDEC), a lipid droplet membrane protein, facilitates lipid droplet fusion and is crucial for adipose tissue expansion, making it a key target for obesity and related metabolic diseases. However, previous research revealed that complete genetic deletion of Cidec in adipose tissues, while reducing fat accumulation, induced severe insulin resistance in high-fat diet (HFD)-fed mice, potentially due to ectopic fat storage in the liver. Given that complete knockout is an extreme approach, partial inhibition holds greater clinical relevance. Therefore, this study aimed to investigate the effects of partial inhibition of CIDEC in adipose tissues on fat accumulation and insulin sensitivity in mice. Using the Cre-LoxP system, we generated adipose Cidec haploinsufficient mice. Under a standard diet, these mice exhibited normal body weight, fat accumulation, and insulin sensitivity. Notably, under HFD conditions, mice with partial Cidec deficiency showed reduced fat accumulation in adipose tissues while hepatic fat accumulation remained unchanged, accompanied by improved insulin sensitivity and increased energy expenditure. Mechanistically, we found partial Cidec deficiency activated thermogenic program in adipocytes in vivo and in vitro through the ATGL-PPARα pathway. In conclusion, adipose CIDEC partial inhibition attenuates HFD-induced obesity and insulin resistance by enhancing ATGL-PPARα-mediated energy expenditure, establishing this approach as a promising therapeutic strategy for obesity and related metabolic diseases.
研究领域:
生物学
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医学
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代谢疾病
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DOI
PubMed
高影响因子
Cell Death & Disease
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2023
·Vol. 14
·期 2
·1-17
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IF 9
Chen Yulian,Jiang Huanguo,Zhan Zhikun,Lu Jindi,Gu Tanwei,Yu Ping,Liang Weimin,Zhang Xi,Liu Shuwen,Bi Huichang,Zhong Shilong,Tang Lan
Converting lipid disturbances in response to energy oversupply into healthy lipid homeostasis is a promising therapy to alleviate hepatosteatosis. Our clinical studies found that a further elevation of triglyceride (TG) in obese patients with the body mass index (BMI) greater than 28 was accompanied by a further reduction of phosphatidylethanolamine (PE). Shorter survival and poor prognosis were shown for the patients with high TG and low PE levels. Liver X receptor alpha ( LXRα ) knockout mice aggravated high-fat diet (HFD)-induced obesity and lipid disorders, making the TG enrichment and the PE decrease more pronounced according to the liver lipidomics analysis. The RNA-seq from mice liver exhibited that these metabolism disorders were attributed to the decline of Atgl (encoding the TG metabolism enzyme ATGL) and Ept1 (encoding the PE synthesis enzyme EPT1) expression. Mechanistic studies uncovered that LXRα activated the ATGL and EPT1 gene via direct binding to a LXR response element (LXRE) in the promoter. Moreover, both the supplement of PE in statin or fibrate therapy, and the LXRα inducer (oridonin) ameliorated cellular lipid deposition and lipotoxicity. Altogether, restoration of lipid homeostasis of TG and PE via the LXRα-ATGL/EPT1 axis may be a potential approach for the management of hepatosteatosis and metabolic syndrome.
研究领域:
分子生物学
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代谢学
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肝病学
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药理学
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DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
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2022
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IF 4.114
Pan Li,Yuwei Chen,Xiumei Ke,Ruoyu Zhang,Ling Zuo,Meng Wang,Zhiwei Chen,Xianqin Luo,Jianwei Wang
Baicalin is a flavonoid compound abundant in multiple edible and medicinal plants such as Scutellaria baicalensis Georgi . In this study, we provide evidence to support the fact that baicalin ameliorates alcohol-induced hepatic steatosis via regulating SREBP1c elicited PNPLA3 competitive binding to ATGL . Results showed that baicalin significantly attenuated the development of metabolic disorders and hepatic steatosis in alcohol-induced rats after four weeks of treatment. It was evident that baicalin treatment significantly normalized the serous contents of hepatic triglyceride (TG), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), and attenuated the increase of hepatic vacuolization and Oil Red O staining area caused by alcohol. Meanwhile, baicalin relieves alcohol-induced hepatic fibrosis by masson staining and RT-qPCR analysis. Mechanistically, alcohol aggravated the nuclear expression of SREBP1c, which contributed to the high expression of PNPLA3 and FASN , thereby enhancing the binding of PNPLA3 to ABHD5 , and indirectly impairing the binding ability between ATGL and ABHD5, ultimately causing a decline in the hydrolysis capacity in liver lipid droplets . As expected, these alcohol-induced pathobolism were reversed by baicalin treatment both in vivo and in vitro . In conclusion, this study has demonstrated that baicalin can protect against alcohol-induced hepatic lipid accumulation by activating hepatic lipolysis via suppressing SREBP1c elicited PNPLA3 competitive binding to ATGL. Baicalin is a promising natural product for preventing alcohol-induced hepatic steatosis.
研究领域:
药理学
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肝病学
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代谢学
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分子生物学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
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2026
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IF 11.3
Jian Chen,Zhixiang Wei,Zixuan Song,Sitong Meng,Jiaqi An,Zhenqun Zhang,Yaning Biao,Muqing Zhang,Yixin Zhang
Background Obesity prevalence is rising, increasing risks of metabolic associated fatty liver disease, diabetes mellitus, and cardiovascular disease. Atractylodin (ATR), a bioactive compound from Atractylodes lancea , exhibits potential against metabolic disorders, but its mechanisms against obesity-driven hepatic steatosis remain unclear. Purpose This study aimed to investigate the therapeutic effects and underlying mechanisms of ATR in ameliorating obesity-associated hepatic steatosis via lipid droplet (LD)-mitochondria interactions. Methods Mice were fed a high-fat diet (HFD) for 12 weeks, followed by administration of ATR or Orlistat for 6 weeks beginning at week 6. Hepatic steatosis and molecular targets were assessed via serum biochemistry, histology, fluorescent staining, and Western blot. AML-12 and HepG2 cells were induced with free fatty acids (FFA) and treated with ATR, Atglistatin (ATGLi), etomoxir (ETO), subjected to CPT1A knockdown, or subjected to PLIN2 overexpression/knockdown. In addition to analyzing key proteins and lipid content by molecular and biochemical methods, LD-mitochondria contacts were visualized by transmission electron microscope and laser confocal fluorescence microscopy. Results ATR significantly ameliorated obesity-associated hepatic steatosis in mice and reduced lipid accumulation in AML-12 and HepG2 cells. Visual analysis confirmed that ATR promoted LD-mitochondria contacts. Molecular analysis showed that ATR regulated proteins for lipolysis and fatty acid oxidation (FAO) in liver. Genetic approaches validated that ATR downregulated PLIN2. Mechanistically, ATR promoted LD-mitochondria interactions, lipolysis, and FAO. The effects may be mediated through the regulation of the PLIN2-ATGL/CPT1A axis. Conclusions ATR ameliorates obesity-associated hepatic steatosis by enhancing lipolysis and FAO. Promoting LD-mitochondria interactions represents a promising therapeutic strategy, with ATR showing potential as a therapeutic agent for obesity.
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PubMed
高影响因子
CELLULAR SIGNALLING
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2023
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IF 4.8
Jinmiao Tian,Lichao Zhang,Xiaoqin La,Xiaxia Fan,Aiping Li,Changxin Wu,Yuxuan An,Shuning Yan,Xiushan Dong,Haitao Wu,Zhuoyu Li
Macrophages in hypoxic regions of advanced colorectal tumors often exhibit M2-type features, but prefer oxygen-consuming lipid catabolism , which is contradictory in oxygen demand and supply. In this study, the results from bioinformatics analysis and intestinal lesions immunohistochemistry of 40 colorectal cancer patients illustrated that glucose-regulatory protein 78 (GRP78) was positively correlated with M2 macrophages. Furthermore, tumor-secreted GRP78 could enter macrophages and polarize them to M2-type. Mechanistically, entered GRP78 located in lipid droplets of macrophages, and elevated protein stabilization of adipose triglyceride lipase ATGL by interacting with it to inhibit its ubiquitination . Increased ATGL promoted the hydrolysis of triglycerides and the production of arachidonic acid (ARA) and docosahexaenoic acid (DHA). Excessive ARA and DHA interacted with PPARγ to encourage its activation, which mediated the M2 polarization of macrophages. In summary, our study showed that secreted GRP78 in the tumor hypoxic microenvironment mediated the domestication of tumor cells to macrophages and maintained tumor immunosuppressive microenvironment by promoting lipolysis, and the lipid catabolism not only provides energy for macrophages but also plays an important role in maintenance of immunosuppressive properties.
研究领域:
肿瘤学
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免疫学
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细胞生物学
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生物化学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Shan Li,Ronghua Guo,Xiang Gao,Yin Wang,Jiaxin Wen,Ting Zhao,Xiaofei Guo,Junhui Li,Shiguo Chen,Duo Li
Fucosylated chondroitin sulfate from Pearsonothuria graeffei (FCS- Pg ), a natural macromolecular polysaccharide, has been proven to prevent obesity, but its underlying molecular mechanism is still unclear. C57BL/6 J mice fed on high fat diet (HFD) were administered FCS- Pg lasting for ten weeks. The results demonstrated that FCS- Pg supplementation reduced body weight with dosage manner compared with HFD group. The expressions of intestinal lipid synthesis related proteins such as cluster of differentiation 36 (CD36) in FCS- Pg group were lower than those in the HFD group. Compared with the normal group, HFD caused gut microbiota disorder in the colon. FCS- Pg supplementation at high dosage restored the gut microbiota composition with higher abundance of Alistipes and Bacteroidetes and lower abundance of Colidextribacter , Bilophila and Firmicutes compared with HFD group. Moreover, FCS- Pg decreased the expression of proteins involved in triglyceride synthesis such as glycerol 3-phosphate dehydrogenase 1 (GPD1) and increased the expression of proteins involved in lipolysis and thermogenesis such as adipose triglyceride lipase (ATGL) and uncoupling protein 1 (UCP1) in the white adipose tissue (WAT) compared with HFD group. In conclusion, our study suggested that FCS- Pg significantly prevented obesity and improved WAT function in HFD-fed mice by regulating intestinal lipid metabolism and microflora composition.
研究领域:
营养学
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分子生物学
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微生物学
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肥胖研究
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代谢学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2022
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IF 5.988
Sa Yang,Shijie Cao,Congyu Li,Jichao Zhang,Chang Liu,Feng Qiu,Ning Kang
Non-alcoholic fatty liver disease (NAFLD) is a major public health problem in many countries. Berberine (BBR) is an effective therapeutic agent in alleviating NAFLD. Berberrubine (BRB) is one of the main active metabolites of BBR, which shows significant anti-obesity and antihypoglycemic effects. However, whether BRB is responsible for the in vivo therapeutic effect and the underlying mechanism of BRB on NAFLD have not been elucidated. In this study, the ability of BRB to ameliorate NAFLD, together with its molecular mechanism, was investigated. The results showed that BRB treatments could significantly improve hepatic steatosis and insulin resistance in high-fat diet (HFD)-fed mice and oleic acid (OA)-treated HepG2 cells. Meanwhile, BBR and BRB treatment similarly prevented lipid accumulation by regulating the protein expression of ATGL, GK, PPARα, CPT-1, ACC1, FAS, and CD36. In addition, compared with BBR, BRB could maintain glucose homeostasis via GLUT2, GSK3β, and G6Pase in HFD-fed mice. Furthermore, the components of the gut microbiota in mice were analyzed by 16S rRNA gene sequencing. BBR and BRB treatment could greatly modify the structure and composition of gut microbiota. At the genus level, BBR and BRB treatment decreased Lactobacillus and Romboutsia , while BBR increased beneficial bacteria, such as Akkermansia and Bacteroides , and BRB increased beneficial bacteria, such as Ileibacterium and Mucispirillum . Altogether, both BRB and BBR were active in alleviating NAFLD in vivo and BRB might be used as a functional material to treat NAFLD clinically.
研究领域:
药理学
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代谢学
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胃肠病学
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微生物学
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DOI
PubMed
高影响因子
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