Upregulation of miR-125b by estrogen protects against non-alcoholic fatty liver in female mice

Zhang, Zhi Chun; Liu, Yan; Xiao, Liuling; Li, Shu Fen; Jiang, Jing; Zhao, Yue; Qian, Shu Wen; Tang, Qi; Li, Xi

doi:10.1016/j.jhep.2015.07.037

Cited by 85 publications

(64 citation statements)

References 37 publications

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“…The cells were washed with water, and stained fat droplets in the cells were examined by light microscopy and photographed. Oil Red O staining and hematoxylin and eosin (H&E) staining of mouse liver tissues were conducted as described previously (21).…”

mentioning

confidence: 99%

Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease

Guo

Zhou

Wei

et al. 2016

Molecular and Cellular Biology

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bNonalcoholic fatty liver disease (NAFLD) has become the most common liver disease, and decreased fatty acid oxidation is one of the important contributors to NAFLD. Mitochondrial trifunctional protein ␣-subunit (MTP␣) functions as a critical enzyme for fatty acid ␤-oxidation, but whether dysregulation of MTP␣ is pathogenically connected to NAFLD is poorly understood. We show that MTP␣ is acetylated at lysine residues 350, 383, and 406 (MTP␣-3K), which promotes its protein stability by antagonizing its ubiquitylation on the same three lysines (MTP␣-3K) and blocking its subsequent degradation. Sirtuin 4 (SIRT4) has been identified as the deacetylase, deacetylating and destabilizing MTP␣. Replacement of MTP␣-3K with either MTP␣-3KR or MTP␣-3KQ inhibits cellular lipid accumulation both in free fatty acid (FFA)-treated alpha mouse liver 12 (AML12) cells and primary hepatocytes and in the livers of high-fat/high-sucrose (HF/HS) diet-fed mice. Moreover, knockdown of SIRT4 could phenocopy the effects of MTP␣-3K mutant expression in mouse livers, and MTP␣-3K mutants more efficiently attenuate SIRT4-mediated hepatic steatosis in HF/HS diet-fed mice. Importantly, acetylation of both MTP␣ and MTP␣-3K is decreased while SIRT4 is increased in the livers of mice and humans with NAFLD. Our study reveals a novel mechanism of MTP␣ regulation by acetylation and ubiquitylation and a direct functional link of this regulation to NAFLD.

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mentioning

confidence: 99%

Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease

Guo

Zhou

Wei

et al. 2016

Molecular and Cellular Biology

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“…Previous research identified that miR-125b transcription was activated by ERα, C/EBPα and Nrf2 in mammal cell lines (Zhang et al, 2015;Romero et al, 2015). To explore which transcription factor regulated pri-miR-125bs expression in zebrafish embryos, we used the JASPAR web service (http://jaspar.genereg.net/cgi-bin/jaspar_db.pl, Relative profile score threshold was 80%) and found several C/EBPα and Cap'n'collar (CNC) family bZip protein (NFE2, Nfe2l2/MAF:NFE2) putative binding sites at the 5′ upstream promoter region (-2 to +1 kb) of mir-125b genes (Johnsen et al, 1998).…”

Section: Origin For Up-regulation Of Mir-125b and Screening For Transmentioning

confidence: 94%

“…In cancer research, miR-125b is associated with tumor suppressor by down-regulating target oncogene (Yueh et al, 2014). Additionally, several studies have examined miR-125b in relationship to metabolic disorders in mice and humans cell lines (Zhang et al, 2015;Tili et al, 2012). miR-125a/b was found to suppress Cd-induced apoptosis by target Bak and caspase-3 directly in LLC-PK1 cells (Chen et al, 2016a,b).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, the specific objective of this study was to probe up-stream mechanisms regulating miR-125b expression changes resulting from TCS exposure to zebrafish (Danio rerio). Although previous researches identified several factors that positively regulate miR-125b expression in mammal cell lines, such as Nrf2, c/EBPα and ERα, whether or not miR-125b is also involved in glucose and lipid metabolism in zebrafish embryo remain uncertain (Tili et al, 2012;Joo et al, 2013;Zhang et al, 2015;Romero et al, 2015). Furthermore, the molecular mechanisms for abnormal expression of miR-125b from TCS exposure and the conservation of miR-125b in vertebrates have not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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Up-stream mechanisms for up-regulation of miR-125b from triclosan exposure to zebrafish (Danio rerio)

et al. 2017

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A B S T R A C TTriclosan (TCS) exposure has widely adverse biological effects such as influencing biological reproduction and endocrine disorders. While some studies have addressed TCS-induced expression changes of miRNAs and their related down-stream target genes, no data are available concerning how TCS impairs miRNA expression leading us to study up-stream regulating mechanisms. Four miRNAs (miR-125b, miR-205, miR-142a and miR-203a) showed differential expression between TCS-exposure treatments and the control group; their functions mainly involved fatty acid synthesis and metabolism. TCS exposure led to the up-regulation of mature miR-125b that was concomitant with consistent changes in pri-mir-125b-1 and pri-mir-125b-3 among its 3 pri-mir-125bs. Upregulation of miR-125b originated from direct shear processes involving the two up-regulated precursors, but not pri-mir-125b2. Increased expression of pri-mir-125b-1 and pri-mir-125b-3 resulted from nfe2l2-and c/ebpα-integration with positive control elements of promoters for the two precursors. The overexpression of transcriptional factors, nfe2l2 and c/ebpα, initiated the promoter activity for the miR-125b precursor. CpG islands and Nfe2l2 were involved in constitutive expression of mir-125b-1 and mir-125b-3. The activities of two promoter regions, −487 to −1 bp for pri-mir-125b1 and −1327 to +14 bp for pri-mir-125b-3 having binding sites for NFE2 and Nfe2l2/MAF:NFE2, were higher than other regions, further demonstrating that the transcriptional factor Nfe2l2 was involved in the regulation of pri-mir-125b1 and pri-mir-125b-3. TCS's estrogen activity resulted from its effects on GPER, a novel membrane receptor, rather than the classical ERα and ERβ. These results explain, to some extent, the up-stream mechanism for miR-125b up-regulation, and also provide a guidance to future mechanistic study on TCS-exposure.

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“…Besides, liver is the main site for lowering serum TC. Steroid hormones, such as estrogen that is closely related to cell cycle alteration in liver (21), also play important roles in hepatic lipid metabolism (22,23). Therefore, we hypothesized that liver may be a target organ of SAK-HV.…”

Section: Ivyspringmentioning

confidence: 99%

SAK-HV Triggered a Short-period Lipid-lowering Biotherapy Based on the Energy Model of Liver Proliferation via a Novel Pathway

Zhang¹,

Huang²,

Jing³

et al. 2017

Theranostics

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The accumulations of excess lipids within liver and serum are defined as non-alcoholic fatty liver disease (NAFLD) and hyperlipemia respectively. Both of them are components of metabolic syndrome that greatly threaten human health. Here, a recombinant fusion protein (SAK-HV) effectively treated NAFLD and hyperlipemia in high-fat-fed ApoE -/- mice, quails and rats within just 14 days. Its triglyceride and cholesterol-lowering effects were significantly better than that of atorvastatin during the observation period. We explored the lipid-lowering mechanism of SAK-HV by the hepatic transcriptome analysis and serials of experiments both in vivo and in vitro . Unexpectedly, SAK-HV triggered a moderate energy and material-consuming liver proliferation to dramatically decrease the lipids from both serum and liver. We provided the first evidence that PGC-1α mediated the hepatic synthesis of female hormones during liver proliferation, and proposed the complement system-induced PGC-1α-estrogen axis via the novel STAT3-C/EBPβ-PGC-1α pathway in liver as a new energy model for liver proliferation. In this model, PGC-1α ignited and fueled hepatocyte activation as an “igniter”; PGC-1α-induced estrogen augmented the energy supply of PGC-1α as an “ignition amplifier”, then triggered the hepatocyte state transition from activation to proliferation as a “starter”, causing triglyceride and cholesterol-lowering effects via PPARα-mediated fatty acid oxidation and LDLr-mediated cholesterol uptake, respectively. Collectively, the SAK-HV-triggered distinctive lipid-lowering strategy based on the new energy model of liver proliferation has potential as a novel short-period biotherapy against NAFLD and hyperlipemia.

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Upregulation of miR-125b by estrogen protects against non-alcoholic fatty liver in female mice

Cited by 85 publications

References 37 publications

Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease

Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease

Up-stream mechanisms for up-regulation of miR-125b from triclosan exposure to zebrafish (Danio rerio)

SAK-HV Triggered a Short-period Lipid-lowering Biotherapy Based on the Energy Model of Liver Proliferation via a Novel Pathway

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