Hepatocyte Kctd17 Inhibition Ameliorates Glucose Intolerance and Hepatic Steatosis Caused by Obesity-induced Chrebp Stabilization

Oh, Ah-Reum; Jeong, Yoseok; Yu, Junjie; Tam, Dao Thi Minh; Kang, Jin Ku; Jung, Young Hoon; Im, Seung‐Soon; Lee, Sang Bae; Ryu, Dongryeol; Pajvani, Utpal B.; Kim, KyeongJin

doi:10.1053/j.gastro.2022.11.019

Cited by 10 publications

(5 citation statements)

References 48 publications

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“…Multiple studies have revealed genes that may be related to the development and prognosis of NASH in recent years [36,37]. In our study, three candidate genes are singled out.Akr1a1, a new mammalian Snitroso-glutathione reductase (GSNO), is associated with chronic hepatitis and hepatocellular carcinoma [38].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Insight Based on Network Analysis Reveals the Effect of Ursolic Acid on Non-Alcoholic Steatohepatitis

Xue

Rao

et al. 2022

Preprint

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Background Non-alcoholic steatohepatitis (NASH) has attracted international attention. However, pharmaceutical treatments are not included in the current guidelines. Ursolic acid (UA) has the potential to treat metabolic disorders. Hence, this study aimed to investigate the impact of UA on NASH. Methods RNA sequencing from our own model mice was performed to detect differentially expressed genes (DEGs) in 12 mouse samples from 4 groups. DEGs were subjected to Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Weighted gene co-expression network analysis (WGCNA) was applied to find modules associated with NASH's pathological characteristics and identified the hub genes in the relevant modules. Hub genes were further identified and the ceRNA network was constructed. In vitro and in vivo experiments were applied to identify the expected mRNAs. Results By comparing NASH mice to Wild type (WT) mice, we performed GO and KEGG enrichment analysis to identify pathways associated with NASH inflammatory metabolic disorders, and by doing the same for NASH mice treated with UA, we identified pathways via which UA may alter. Based on WGCNA, the modules associated with the pathological changes of NASH, as well as the hub genes in each module were identified. A ceRNA network was successfully constructed. RT-PCR results showed that Akr1a1 and Chchd2 were protective factors against NASH, and Ndufb9 was a risk factor. The level of ROS detected by flow cytometry indicated that UA could alleviate oxidative stress. Conclusion Akr1a1, Chchd2, and Ndufb9 were essential for the therapeutic effects of UA on NASH and the ceRNA network might act as prospective therapeutic and diagnostic biomarker targets.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic Insight Based on Network Analysis Reveals the Effect of Ursolic Acid on Non-Alcoholic Steatohepatitis

Xue

Rao

et al. 2022

Preprint

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“…Notably, there is evidence that the post-translational modification of ChREBP is mainly mediated by glycosylation. A recent study showed that O-GlcNAc glycosylation increased the stability of ChREBP, promoted the expression of regulated lipogenic target genes, and aggravated hepatic steatosis in a MASLD mouse model ( 82 ). Future research on specific drugs should focus on regulating the post-translational modification of ChREBP to fully explore its therapeutic potential in MASLD.…”

Section: Medications Aimed At Regulating Lipid Metabolism In Masldmentioning

confidence: 99%

“…Another clinical study suggested that PF-06835919 was dose-dependent in the treatment of MASLD. The high-dose PF-06835919 achieved the main clinical end point (the reduction of total liver fat), while the low-dose PF-06835919 (75 mg) did not exhibit any significant therapeutic effect (80). The exploration of the potential therapeutic range of ketohexokinase inhibitors will be extended through continued research on MASH patients (81).…”

Section: Chrebpmentioning

confidence: 99%

Unmasking the enigma of lipid metabolism in metabolic dysfunction-associated steatotic liver disease: from mechanism to the clinic

Rao,

Peng,

et al. 2023

Front. Med.

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Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly defined as non-alcoholic fatty liver disease (NAFLD), is a disorder marked by the excessive deposition of lipids in the liver, giving rise to a spectrum of liver pathologies encompassing steatohepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma. Despite the alarming increase in its prevalence, the US Food and Drug Administration has yet to approve effective pharmacological therapeutics for clinical use. MASLD is characterized by the accretion of lipids within the hepatic system, arising from a disarray in lipid provision (whether through the absorption of circulating lipids or de novo lipogenesis) and lipid elimination (via free fatty acid oxidation or the secretion of triglyceride-rich lipoproteins). This disarray leads to the accumulation of lipotoxic substances, cellular pressure, damage, and fibrosis. Indeed, the regulation of the lipid metabolism pathway is intricate and multifaceted, involving a myriad of factors, such as membrane transport proteins, metabolic enzymes, and transcription factors. Here, we will review the existing literature on the key process of lipid metabolism in MASLD to understand the latest progress in this molecular mechanism. Notably, de novo lipogenesis and the roles of its two main transcription factors and other key metabolic enzymes are highlighted. Furthermore, we will delve into the realm of drug research, examining the recent progress made in understanding lipid metabolism in MASLD. Additionally, we will outline prospective avenues for future drug research on MASLD based on our unique perspectives.

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“…KCTD17 expression is increased in the livers of obese mice and patients with NAFLD/nonalcoholic steatohepatitis (NASH), leading to the degradation of pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) to prolong insulin signaling by dephosphorylating AKT 97 . Hepatocyte KCTD17 deletion in HFD-fed mice improved glucose intolerance and fatty liver by increasing carbohydrate response element-binding protein (ChREBP) protein stability via the degradation of O-GlcNAcase (OGA), suggesting that KCTD17 is a key regulatory node in multiple liver metabolic processes and a novel therapeutic option for the treatment of obesity-induced insulin resistance and NAFLD 98 . Additionally, its expression levels are increased in white adipose tissue in obese mice compared to lean control mice.…”

Section: Roles Of Ring-finger E3 Ligases and Their Adaptors In Metabo...mentioning

confidence: 99%

Targeting E3 ubiquitin ligases and their adaptors as a therapeutic strategy for metabolic diseases

Jeong,

Oh,

Jung

et al. 2023

Exp Mol Med

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Posttranslational modification of proteins via ubiquitination determines their activation, translocation, dysregulation, or degradation. This process targets a large number of cellular proteins, affecting all biological pathways involved in the cell cycle, development, growth, and differentiation. Thus, aberrant regulation of ubiquitination is likely associated with several diseases, including various types of metabolic diseases. Among the ubiquitin enzymes, E3 ubiquitin ligases are regarded as the most influential ubiquitin enzymes due to their ability to selectively bind and recruit target substrates for ubiquitination. Continued research on the regulatory mechanisms of E3 ligases and their adaptors in metabolic diseases will further stimulate the discovery of new targets and accelerate the development of therapeutic options for metabolic diseases. In this review, based on recent discoveries, we summarize new insights into the roles of E3 ubiquitin ligases and their adaptors in the pathogenesis of metabolic diseases by highlighting recent evidence obtained in both human and animal model studies.

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Hepatocyte Kctd17 Inhibition Ameliorates Glucose Intolerance and Hepatic Steatosis Caused by Obesity-induced Chrebp Stabilization

Cited by 10 publications

References 48 publications

Transcriptomic Insight Based on Network Analysis Reveals the Effect of Ursolic Acid on Non-Alcoholic Steatohepatitis

Transcriptomic Insight Based on Network Analysis Reveals the Effect of Ursolic Acid on Non-Alcoholic Steatohepatitis

Unmasking the enigma of lipid metabolism in metabolic dysfunction-associated steatotic liver disease: from mechanism to the clinic

Targeting E3 ubiquitin ligases and their adaptors as a therapeutic strategy for metabolic diseases

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