Hepatocyte SH3RF2 Deficiency Is a Key Aggravator for NAFLD

Yang, Xia; Sun, Dating; Xiang, Hui; Wang, Sichen; Huang, Yaji; Li, Ling; Xu, Cheng; Liu, Hui; Hu, Fengjiao; Cheng, Yun; Ma, Tengfei; Hu, Manli; Tian, Han; Shen, Tian; Zhou, Yan; Zhang, Peng; Zhang, Xiaojing; Ji, Yan‐Xiao; Hu, Yufeng; Li, Hongliang; She, Zhi‐Gang

doi:10.1002/hep.31863

Cited by 15 publications

(9 citation statements)

References 37 publications

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“…Notably, Jin et al ( 2017 ) reported that loss of LBP can attenuate the development of WSD-induced NAFLD, which is inconsistent with our results. It is well established that the clinical pathogenesis and characteristics of NAFLD are highly heterogeneous ( Yang et al, 2021 ). Thus, different diets may trigger different hepatic pathological features, mimicking different clinical states of NAFLD, which may explain the different influences of LBP deficiency on NAFLD.…”

Section: Discussionmentioning

confidence: 99%

Loss of LBP triggers lipid metabolic disorder through H3K27 acetylation-mediated C/EBPβ-SCD activation in non-alcoholic fatty liver disease

Zhu,

Meng,

et al. 2024

Zoological Research

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Non-alcoholic fatty liver disease (NAFLD) is associated with mutations in lipopolysaccharide-binding protein ( LBP ), but the underlying epigenetic mechanisms remain understudied. Herein, LBP -/- rats with NAFLD were established and used to conduct integrative targeting-active enhancer histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation coupled with high-throughput and transcriptomic sequencing analysis to explore the potential epigenetic pathomechanisms of active enhancers of NAFLD exacerbation upon LBP deficiency. Notably, LBP -/- reduced the inflammatory response but markedly aggravated high-fat diet (HFD)-induced NAFLD in rats, with pronounced alterations in the histone acetylome and regulatory transcriptome. In total, 1 128 differential enhancer-target genes significantly enriched in cholesterol and fatty acid metabolism were identified between wild-type (WT) and LBP -/- NAFLD rats. Based on integrative analysis, CCAAT/enhancer-binding protein β (C/EBPβ) was identified as a pivotal transcription factor (TF) and contributor to dysregulated histone acetylome H3K27ac, and the lipid metabolism gene SCD was identified as a downstream effector exacerbating NAFLD. This study not only broadens our understanding of the essential role of LBP in the pathogenesis of NAFLD from an epigenetics perspective but also identifies key TF C/EBPβ and functional gene SCD as potential regulators and therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Loss of LBP triggers lipid metabolic disorder through H3K27 acetylation-mediated C/EBPβ-SCD activation in non-alcoholic fatty liver disease

Zhu,

Meng,

et al. 2024

Zoological Research

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“…The liver is a major organ for systemic cholesterol and fructose metabolism, and recent studies have indicated that liver metastatic CRC cells have increased fructose and cholesterol metabolism, and genetically or pharmacologically inhibiting these metabolic switches could suppress liver metastasis of CRC [ 47 , 58 ]. NAFLD as a systemic metabolic stress enhanced DNL in hepatocytes via multiple mechanisms, such as upregulating of USP14 to deubiquitinate FASN and promote its stability, and depleting SH3RF2 to stabilize ATP citrate lyase (ACLY) [ 59 , 60 ]. In this study, we found that the NAFLD hepatic metabolic microenvironment could also enhance de novo palmitate biosynthesis in liver metastatic CRC cells and that enriched intracellular palmitate bioavailability could promote cancer cell stemness by facilitating palmitoylation of EGFR to promote its stability and PM localization.…”

Section: Discussionmentioning

confidence: 99%

Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation

Zhang,

Dong

et al. 2024

Cell Death Discov.

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Liver metastasis is the major reason for most of colorectal cancer (CRC) related deaths. Accumulating evidence indicates that CRC patients with non-alcoholic fatty liver disease (NAFLD) are at a greater risk of developing liver metastasis. With the growing prevalence of NAFLD, a better understanding of the molecular mechanism in NAFLD-driven CRC liver metastasis is needed. In this study, we demonstrated that NAFLD facilitated CRC liver metastasis as a metabolic disorder and promoted the stemness of metastatic CRC cells for their colonization and outgrowth in hepatic niches. Metabolically, the lipid-rich microenvironment in NAFLD activated de novo palmitate biosynthesis in metastatic CRC cells via upregulating fatty acid synthase (FASN). Moreover, increased intracellular palmitate bioavailability promoted EGFR palmitoylation to enhance its protein stability and plasma membrane localization. Furthermore, we demonstrated that the FDA-approved FASN inhibitor orlistat could reduce NAFLD-activated endogenous palmitate production, thus inhibiting palmitoylation of EGFR to suppress CRC cell stemness and restrict liver metastasis in synergy with conventional chemotherapy. These findings reveal that the NAFLD metabolic microenvironment boosts endogenous palmitate biosynthesis in metastatic CRC cells and promotes cell stemness via EGFR palmitoylation, and FASN inhibitor orlistat could be a candidate adjuvant drug to suppress liver metastasis in CRC patients with NAFLD.

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“…The liver samples were collected from patients undergoing liver biopsy, liver surgery or liver transplantation. The exclusion criteria were described as follows: the male and female patients with drinking more than 140 or 70 g in a week respectively, using a drug or toxin with liver damage, viral infection or other liver disease were eliminated 27,28 . The study was authorized by the institutional ethics committee of Shandong provincial hospital and followed the Declaration of Helsinki.…”

Section: Methodsmentioning

confidence: 99%

“…The exclusion criteria were described as follows: the male and female patients with drinking more than 140 or 70 g in a week respectively, using a drug or toxin with liver damage, viral infection or other liver disease were eliminated. 27,28 The study was authorized by the institutional ethics committee of Shandong provincial hospital and followed the Declaration of Helsinki. NAFLD activity score (NAS) following the roles: NAS ≥ 3 or 5 were sorted out as NAFLD and NASH respectively.…”

Section: Human Liver Samplesmentioning

confidence: 99%

Mitochondrial general control of amino acid synthesis 5 like 1 promotes nonalcoholic steatohepatitis development through ferroptosis‐induced formation of neutrophil extracellular traps

Xiong

Yan

et al. 2023

Clinical & Translational Med

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Background Mitochondria play central roles in metabolic diseases including nonalcoholic steatohepatitis (NASH). However, how mitochondria regulate NASH progression remains largely unknown. Our previous findings demonstrate that mitochondrial general control of amino acid synthesis 5 like 1 (GCN5L1) is associated with mitochondrial metabolism. Nevertheless, the roles of GCN5L1 in NASH are unclear. Aims and methods The GCN5L1 expression was detected in the fatty livers of NASH patients and animals. Hepatocyte‐specific GCN5L1 deficiency or overexpression mice were used to induce NASH models by feeding with a high‐fat/high‐cholesterol or methionine‐choline deficient diet. The molecular mechanisms underlying GCN5L1‐regulated NASH were further explored and verified in mice. Results and conclusions GCN5L1 expression was increased in NASH patients. Upregulated GCN5L1 level was also illustrated in NASH mice. Mice with hepatocyte‐specific GCN5L1 conditional knockout improved the inflammatory response compared to GCN5L1flox/flox mice. However, overexpression of mitochondrial GCN5L1 augmented the inflammatory response. Mechanically, GCN5L1 acetylated CypD and enhanced its binding with ATP5B, which induced the opening of mitochondrial permeability transition pores and the release of mitochondrial ROS into the cytoplasm. The increased ROS promoted ferroptosis of hepatocytes and induced accumulation of high mobility group box 1 in the microenvironment, which recruited neutrophils and induced the generation of neutrophil extracellular traps (NETs). NETs block impaired GCN5L1‐induced NASH progression. Furthermore, the upregulation of GCN5L1 in NASH was contributed by lipid overload‐induced endoplasmic reticulum stress. Together, mitochondrial GCN5L1 has a vital function in promoting NASH progression by regulating oxidative metabolism and the hepatic inflammatory microenvironment. Thus, GCN5L1 might be a potential intervention target in NASH treatment.

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Hepatocyte SH3RF2 Deficiency Is a Key Aggravator for NAFLD

Cited by 15 publications

References 37 publications

Loss of <i>LBP</i> triggers lipid metabolic disorder through H3K27 acetylation-mediated C/EBPβ-<i>SCD</i> activation in non-alcoholic fatty liver disease

Loss of <i>LBP</i> triggers lipid metabolic disorder through H3K27 acetylation-mediated C/EBPβ-<i>SCD</i> activation in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation

Mitochondrial general control of amino acid synthesis 5 like 1 promotes nonalcoholic steatohepatitis development through ferroptosis‐induced formation of neutrophil extracellular traps

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