ArticleHepatology (Baltimore, Md.)2012
Glucokinase links Krüppel-like factor 6 to the regulation of hepatic insulin sensitivity in nonalcoholic fatty liver disease.
Article in Hepatology (Baltimore, Md.), 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 65 citations in OpenAlex.
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- Identification of potential metabolic biomarkers and immune cell infiltration for metabolic associated steatohepatitis by bioinformatics analysis and machine learning.Scientific reports · 2025Article
- Genome-wide association study of the fatty liver index in the Taiwanese population reveals shared and population-specific genetic risk factors across ethnicities.Cell & bioscience · 2025Article
- Alternative splicing: hallmark and therapeutic opportunity in metabolic liver disease.Gastroenterology report · 2025Review
- Hepatic glucose metabolism in the steatotic liver.Nature reviews. Gastroenterology & hepatology · 2024Review
- Specificity Proteins (SP) and Krüppel-like Factors (KLF) in Liver Physiology and Pathology.International journal of molecular sciences · 2023Review
- Styrylpyrones fromAntioxidants (Basel, Switzerland) · 2022Article
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- The Emerging Factors and Treatment Options for NAFLD-Related Hepatocellular Carcinoma.Cancers · 2021Review
- Genetic Polymorphisms and Clinical Features in Diabetic Patients With Fatty Liver: Results From a Single-Center Experience in Southern Italy.Frontiers in medicine · 2021Article
- Alternative RNA Splicing in Fatty Liver Disease.Frontiers in endocrinology · 2021Review
- Review
- Assessment of mitochondrial function in metabolic dysfunction-associated fatty liver disease using obese mouse models.Zoological research · 2020Article
- Validating candidate biomarkers for different stages of non-alcoholic fatty liver disease.Medicine · 2020Observational
- Klf6 protects β-cells against insulin resistance-induced dedifferentiation.Molecular metabolism · 2020Article
- From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options.JHEP reports : innovation in hepatology · 2019Review
- Review
- Association of TM6SF2 rs58542926 gene polymorphism with the risk of non-alcoholic fatty liver disease and colorectal adenoma in Chinese Han population.BMC biochemistry · 2019Article
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Authors and funding
22 authors at 7 institutions in 5 countries.
Funding
Abstract
unlabelledThe polymorphism, KLF6-IVS1-27A, in the Krüppel-like factor 6 (KLF6) transcription factor gene enhances its splicing into antagonistic isoforms and is associated with delayed histological progression of nonalcoholic fatty liver disease (NAFLD). To explore a potential role for KLF6 in the development of insulin resistance, central to NAFLD pathogenesis, we genotyped KLF6-IVS1-27 in healthy subjects and assayed fasting plasma glucose (FPG) and insulin sensitivities. Furthermore, we quantified messenger RNA (mRNA) expression of KLF6 and glucokinase (GCK), as an important mediator of insulin sensitivity, in human livers and in liver tissues derived from a murine Klf6 knockdown model (DeltaKlf6). Klf6 overexpression studies in a mouse hepatocyte line were utilized to mechanistically link KLF6 with Gck promoter activity. KLF6-IVS1-27Gwt (i.e., less KLF6 splicing) was associated with stepwise increases in FPG and insulin and reduced hepatic insulin sensitivity. KLF6 binds to the liver-specific Gck promoter and activates a GCK promoter-reporter, identifying GCK as a KLF6 direct transcriptional target. Accordingly, in DeltaKlf6 hepatocytes Gck expression was reduced and stable transfection of Klf6 led to up-regulation of Gck. GCK and KLF6 mRNAs correlate directly in human NAFLD tissues and immunohistochemistry studies confirm falling levels of both KLF6 and GCK in fat-laden hepatocytes. In contrast to full-length KLF6, splice variant KLF6-SV1 increases in NAFLD hepatocytes and inversely correlates with glucokinase regulatory protein, which negatively regulates GCK activity.
conclusionKLF6 regulation of GCK contributes to the development of hepatic insulin resistance. The KLF6-IVS1-27A polymorphism, which generates more KLF6-SV1, combats this, lowering hepatic insulin resistance and blood glucose.
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