p300 promotes hepatic lipid accumulation in dyslipidemia by regulating SREBP-1c acetylation

NUHU Abdul-Rauf Nyewneh; LI Xiaoli; FANG Lu; CAI Yongqing; CHEN Fei; YUAN Lie; YANG Xiong; JIANG Qingsong; LIU Yinbo; LIU Chao; ZHONG Peiling; ZENG Menghua

doi:10.16016/j.2097-0927.202508046

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p300 promotes hepatic lipid accumulation in dyslipidemia by regulating SREBP-1c acetylation

Basic Medicine | 更新时间：2025-11-28

- p300 promotes hepatic lipid accumulation in dyslipidemia by regulating SREBP-1c acetylation
- Journal of Army Medical University Vol. 47, Issue 22, Pages: 2735-2748(2025)
- 作者机构：
  
  1.重庆医科大学药学院，重庆
  2.重庆医科大学附属第一医院胃肠外科，重庆
  3.重庆高校生物化学与分子药理学重点实验室，重庆
  4.陆军军医大学大坪医院药剂科，重庆
  5.达州市中西医结合医院药学科，四川达州
- 作者简介：
  
  ZHONG Peiling， E-mail： zhongpeiling33@163.com
  ZENG Menghua， E-mail： 202891@cqmu.edu.cn
- 基金信息：
  
  the General Project of Natural Science Foundation of Chongqing(cstc2021jcyj-msxmX0173;CSTB2024NSCQ-MSX1180);the Sichuan Provincial Special Project of Central Guidance for Regional Scientific and Technological Development(2023ZYD0283);the Project of Undergraduate Innovation and Entrepreneurship Training Program of Chongqing(202510631115)
- DOI：10.16016/j.2097-0927.202508046
  CLC： R341;R394.3;R575.5
- Received：18 August 2025，
  
  Revised：2025-10-25，
  
  Accepted：03 November 2025，
  
  Published：30 November 2025
- 稿件说明：
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Abdul-Rauf Nyewneh Nuhu，李小丽，方路，等.p300在脂代谢紊乱中通过调控SREBP-1c乙酰化促进肝细胞脂质蓄积［J］.陆军军医大学学报，2025，47（22）：2735-2748.DOI：10.16016/j.2097-0927.202508046.

NUHU A R N，LI X L，FANG L，et al.p300 promotes hepatic lipid accumulation in dyslipidemia by regulating SREBP-1c acetylation［J］.J Army Med Univ，2025，47（22）：2735-2748.DOI：10.16016/j.2097-0927.202508046.
Abdul-Rauf Nyewneh Nuhu，李小丽，方路，等.p300在脂代谢紊乱中通过调控SREBP-1c乙酰化促进肝细胞脂质蓄积［J］.陆军军医大学学报，2025，47（22）：2735-2748.DOI：10.16016/j.2097-0927.202508046. DOI：

NUHU A R N，LI X L，FANG L，et al.p300 promotes hepatic lipid accumulation in dyslipidemia by regulating SREBP-1c acetylation［J］.J Army Med Univ，2025，47（22）：2735-2748.DOI：10.16016/j.2097-0927.202508046. DOI：

摘要

目的

探讨p300在脂质代谢紊乱中的作用。

方法

通过生物信息学分析

p300

在脂代谢紊乱相关疾病中的表达及其与

SREBP-1c

及下游脂代谢酶的相关性；通过免疫荧光染色法检测p300在不同严重程度非酒精性脂肪肝（non-alcoholic fatty liver disease， NAFLD）患者肝脏中的表达情况；在体内，通过高脂饮食（high fat diet， HFD）喂养雄性C57BL/6J小鼠12周建立脂代谢紊乱小鼠模型，采用Western blot检测HFD小鼠肝脏中p300表达水平；在体外，建立游离脂肪酸（free fatty acids， FFA）诱导的HepG2/AML-12脂代谢紊乱细胞模型，通过siRNA敲低

p300

后，观察其对细胞内TC、TG、脂质沉积以及活性氧（reactive oxygen species， ROS）水平的影响。

结果

在临床上，p300在脂代谢紊乱疾病中高表达，且其表达水平与NAFLD的严重程度成正相关（

0.05），且GSEA分析显示

p300

表达与脂肪酸代谢、胆固醇稳态、脂肪生成、PPAR信号通路及过氧化物酶体通路显著相关。在体内，p300在HFD喂养小鼠的肝脏中显著上调（

0.01）；在体外，FFA刺激后HepG2及AML-12细胞中p300表达显著升高（

0.01），而敲低

p300

可显著减少细胞内TG、TC含量（

0.01）及脂滴沉积，并且敲低

p300

逆转了FFA诱导的ROS水平升高（

0.01）。此外，

p300

与

SREBP-1c

表达及其下游合成代谢相关酶呈正相关。

结论

p300可能通过乙酰化激活SREBP-1c并调控下游脂代谢酶，影响脂质合成及氧化应激促进肝细胞脂质蓄积，可能是脂代谢紊乱相关疾病治疗的潜在靶点。

Abstract

Objective

To investigate the role of p300 in lipid metabolism disorders.

Methods

Bioinformatics analysis was performed to analyze the expression patterns of

p300

in lipid metabolism disorder-related diseases and its correlation with

SREBP-1c

and downstream lipid metabolic enzymes. Immunofluorescence assay was used to detect the expression of p300 in the liver tissues of the patients with varying disease severity of non-alcoholic fatty liver disease (NAFLD). A mouse model of lipid metabolism disorder was established in male C57BL/6J mice by feeding high-fat diet (HFD) for 12 weeks. Western blotting was employed to assess p300 expression level in the liver tissues of HFD-fed mice. A cell model of lipid metabolism disorder was established in HepG2/AML-12 cells induced with free fatty acid (FFA). The effects of siRNA-mediated knockdown of

p300

was observed to measure the levels of intracellular total cholesterol (TC) and triglyceride (TG)

lipid deposition

and production of reactive oxygen species (ROS).

Results

Clinically

p300 was highly expressed in lipid metabolism disorders

and its level was positively correlated with NAFLD severity (

0.05). Gene Set Enrichment Analysis (GSEA) revealed that

p300

expression was significantly associated with fatty acid metabolism

cholesterol homeostasis

lipogenesis

PPAR signaling pathway

and peroxisome pathway.

In vivo

p300 was significantly up-regulated in the livers of HFD-fed mice (

0.01).

In vitro

FFA stimulation markedly increased p300 expression in both HepG2 and AML-12 cells (

0.01)

whereas

p300

knockdown significantly reduced intracellular TG and TC levels (

0.01)

attenuated lipid droplet accumulation

and reversed FFA-induced ROS elevation (

0.01). Furthermore

p300

expression was positively correlated with the expression of

SREBP-1c

and its downstream key lipid synthesis enzymes.

Conclusion

p300 may promote hepatic lipid accumulation by acetylating and activating SREBP-1c and regulating downstream lipid metabolic enzymes

thereby affecting lipid synthesis and oxidative stress. These findings suggest that p300 may be a potential therapeutic target for lipid metabolism disorder-related diseases.

关键词

Keywords

references

YOON H ， SHAW J L ， HAIGIS M C ， et al . Lipid metabolism in sickness and in health： Emerging regulators of lipotoxicity ［J］. Mol Cell ， 2021 ， 81 （ 18 ）： 3708 - 3730 . DOI： 10.1016/j.molcel.2021.08.027 http://dx.doi.org/10.1016/j.molcel.2021.08.027 .

GÓRECKA W ， BEREZOVSKA D ， MROZIŃSKA M ， et al . Biological and biosimilar medicines in contemporary pharmacotherapy for metabolic syndrome ［J］. Pharmaceutics ， 2025 ， 17 （ 6 ）： 768 . DOI： 10.3390/pharmaceutics17060768 http://dx.doi.org/10.3390/pharmaceutics17060768 .

MEJÍA-GUZMÁN J E ， BELMONT-HERNÁNDEZ R A ， CHÁVEZ-TAPIA N C ， et al . Metabolic-dysfunction-associated steatotic liver disease： molecular mechanisms， clinical implications， and emerging therapeutic strategies ［J］. Int J Mol Sci ， 2025 ， 26 （ 7 ）： 2959 . DOI： 10.3390/ijms26072959 http://dx.doi.org/10.3390/ijms26072959 .

LUCACIU R L ， COSTE S C ， HANGAN A C ， et al . Pathogenesis and clinical management of metabolic dysfunction-associated steatotic liver disease ［J］. Int J Mol Sci ， 2025 ， 26 （ 12 ）： 5717 . DOI： 10.3390/ijms26125717 http://dx.doi.org/10.3390/ijms26125717 .

DANCY B M ， COLE P A . Protein lysine acetylation by p300/CBP ［J］. Chem Rev ， 2015 ， 115 （ 6 ）： 2419 - 2452 . DOI： 10.1021/cr500452k http://dx.doi.org/10.1021/cr500452k .

OGRYZKO V V ， SCHILTZ R L ， RUSSANOVA V ， et al . The transcriptional coactivators p300 and CBP are histone acetyltransferases ［J］. Cell ， 1996 ， 87 （ 5 ）： 953 - 959 . DOI： 10.1016/S0092-8674（00）82001-2 http://dx.doi.org/10.1016/S0092-8674（00）82001-2 .

WAN W ， YOU Z Y ， XU Y F ， et al . mTORC1 phosphorylates acetyltransferase p300 to regulate autophagy and lipogenesis ［J］. Mol Cell ， 2017 ， 68 （ 2 ）： 323 - 335.e6 . DOI： 10.1016/j.molcel.2017.09.020 http://dx.doi.org/10.1016/j.molcel.2017.09.020 .

PONUGOTI B ， KIM D H ， XIAO Z ， et al . SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism ［J］. J Biol Chem ， 2010 ， 285 （ 44 ）： 33959 - 33970 . DOI： 10.1074/jbc.M110.122978 http://dx.doi.org/10.1074/jbc.M110.122978 .

LI Q ， PENG H ， FAN H ， et al . The LIM protein Ajuba promotes adipogenesis by enhancing PPARγ and p300/CBP interaction ［J］. Cell Death Differ ， 2016 ， 23 （ 1 ）： 158 - 168 . DOI： 10.1038/cdd.2015.83 http://dx.doi.org/10.1038/cdd.2015.83 .

ZHOU J L ， LU Y ， JIA Y J ， et al . Ketogenic diet ameliorates lipid dysregulation in type 2 diabetic mice by downregulating hepatic pescadillo 1 ［J］. Mol Med ， 2022 ， 28 （ 1 ）： 1 . DOI： 10.1186/s10020-021-00429-6 http://dx.doi.org/10.1186/s10020-021-00429-6 .

JANG J H ， LEE J W ， CHO M J ， et al . KLHL3 deficiency in mice ameliorates obesity， insulin resistance， and nonalcoholic fatty liver disease by regulating energy expenditure ［J］. Exp Mol Med ， 2022 ， 54 （ 8 ）： 1250 - 1261 . DOI： 10.1038/s12276-022-00833-w http://dx.doi.org/10.1038/s12276-022-00833-w .

WANG Q ， SONG W Y ， TIAN Y M ， et al . Targeted lipidomics reveal the effect of perchlorate on lipid profiles in liver of high-fat diet mice ［J］. Front Nutr ， 2022 ， 9 ： 837601 . DOI： 10.3389/fnut.2022.837601 http://dx.doi.org/10.3389/fnut.2022.837601 .

MI K W ， CHEN Z G ， HE J ， et al . P300-mediated ARRB1 lactylation promotes mitochondrial dysfunction and neuronal apoptosis in subarachnoid hemorrhage via upregulating S100A9 ［J］. Neurochem Res ， 2025 ， 50 （ 3 ）： 174 . DOI： 10.1007/s11064-025-04426-7 http://dx.doi.org/10.1007/s11064-025-04426-7 .

PENG Y L ， WANG Y ， TANG N ， et al . Andrographolide inhibits breast cancer through suppressing COX-2 expression and angiogenesis via inactivation of p300 signaling and VEGF pathway ［J］. J Exp Clin Cancer Res ， 2018 ， 37 （ 1 ）： 248 . DOI： 10.1186/s13046-018-0926-9 http://dx.doi.org/10.1186/s13046-018-0926-9 .

MINAMI E ， SASA K ， YAMADA A ， et al . Lactate-induced histone lactylation by p300 promotes osteoblast differentiation ［J］. PLoS One ， 2023 ， 18 （ 12 ）： e0293676 . DOI： 10.1371/journal.pone.0293676 http://dx.doi.org/10.1371/journal.pone.0293676 .

CAI L Y ， CHEN S J ， XIAO S H ， et al . Targeting p300/CBP attenuates hepatocellular carcinoma progression through epigenetic regulation of metabolism ［J］. Cancer Res ， 2021 ， 81 （ 4 ）： 860 - 872 . DOI： 10.1158/0008-5472.CAN-20-1323 http://dx.doi.org/10.1158/0008-5472.CAN-20-1323 .

CUI A Y ， XUE Y Q ， SU W T ， et al . Glucose regulation of adipose tissue browning by CBP/p300- and HDAC3-mediated reversible acetylation of CREBZF ［J］. Proc Natl Acad Sci U S A ， 2024 ， 121 （ 16 ）： e2318935121 . DOI： 10.1073/pnas.2318935121 http://dx.doi.org/10.1073/pnas.2318935121 .

NGUYEN P ， VALANEJAD L ， CAST A ， et al . Elimination of age-associated hepatic steatosis and correction of aging phenotype by inhibition of cdk4-C/EBPα-p300 axis ［J］. Cell Rep ， 2018 ， 24 （ 6 ）： 1597 - 1609 . DOI： 10.1016/j.celrep.2018.07.014 http://dx.doi.org/10.1016/j.celrep.2018.07.014 .

LIANG J J ， XU C ， XU J ， et al . PPARα senses bisphenol S to trigger EP300-mediated autophagy blockage and hepatic steatosis ［J］. Environ Sci Technol ， 2023 ， 57 （ 51 ）： 21581 - 21592 . DOI： 10.1021/acs.est.3c05010 http://dx.doi.org/10.1021/acs.est.3c05010 .

CHUNG S ， HWANG J T ， PARK J H ， et al . Free fatty acid-induced histone acetyltransferase activity accelerates lipid accumulation in HepG2 cells ［J］. Nutr Res Pract ， 2019 ， 13 （ 3 ）： 196 - 204 . DOI： 10.4162/nrp.2019.13.3.196 http://dx.doi.org/10.4162/nrp.2019.13.3.196 .

ZHONG S S ， LI L X ， SHEN X ， et al . An update on lipid oxidation and inflammation in cardiovascular diseases ［J］. Free Radic Biol Med ， 2019 ， 144 ： 266 - 278 . DOI： 10.1016/j.freeradbiomed.2019.03.036 http://dx.doi.org/10.1016/j.freeradbiomed.2019.03.036 .

GIANDOMENICO V ， SIMONSSON M ， GRÖNROOS E ， et al . Coactivator-dependent acetylation stabilizes members of the SREBP family of transcription factors ［J］. Mol Cell Biol ， 2003 ， 23 （ 7 ）： 2587 - 2599 . DOI： 10.1128/MCB.23.7.2587-2599.2003 http://dx.doi.org/10.1128/MCB.23.7.2587-2599.2003 .

OLINER J D ， ANDRESEN J M ， HANSEN S K ， et al . SREBP transcriptional activity is mediated through an interaction with the CREB-binding protein ［J］. Genes Dev ， 1996 ， 10 （ 22 ）： 2903 - 2911 . DOI： 10.1101/gad.10.22.2903 http://dx.doi.org/10.1101/gad.10.22.2903 .

HO L ， YOUNG L ， JANG H ， et al . Ring finger protein20 regulates hepatic lipid metabolism through protein kinase A-dependent sterol regulatory element binding protein1c degradation ［J］. Hepatology ， 2014 ， 60 （ 3 ）： 844 - 857 . DOI： 10.1002/hep.27011 http://dx.doi.org/10.1002/hep.27011 .

KORCZYNSKA J ， STELMANSKA E ， NOGALSKA A ， et al . Upregulation of lipogenic enzymes genes expression in white adipose tissue of rats with chronic renal failure is associated with higher level of sterol regulatory element binding protein-1 ［J］. Metabolism ， 2004 ， 53 （ 8 ）： 1060 - 1065 . DOI： 10.1016/j.metabol.2004.02.015 http://dx.doi.org/10.1016/j.metabol.2004.02.015 .

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