Krüppel-like factor 15 in liver diseases: Insights into metabolic reprogramming

Chen, Hao; Li, Lanlan; Du, Yan

doi:10.3389/fphar.2023.1115226

Cited by 5 publications

(2 citation statements)

References 95 publications

(104 reference statements)

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“…The significant decrease in the levels of BCAA pathway enzymes in FLC suggested that their transcription may be reduced. Krüppel-like factor 15 (KLF15) is an important transcriptional regulator of metabolic gene expression in the liver, including BCAA catabolism and urea cycle genes 31,50,51 . To investigate whether KLF15 plays a role in FLC metabolism, we first probed for KLF15 in lysates from FLC patients by Western blot.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial Calcium Signaling Regulates Branched-Chain Amino Acid Catabolism in Fibrolamellar Carcinoma

Marsh,

MacEwen,

Chea

et al. 2024

Preprint

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Metabolic adaptations in response to changes in energy supply and demand are essential for survival. The mitochondrial calcium uniporter coordinates metabolic homeostasis by regulating TCA cycle activation, mitochondrial fatty acid oxidation and cellular calcium signaling. However, a comprehensive analysis of uniporter-regulated mitochondrial metabolic pathways has remained unexplored. Here, we investigate the metabolic consequences of uniporter loss- and gain-of-function, and identify a key transcriptional regulator that mediates these effects. Using gene expression profiling and proteomic, we find that loss of uniporter function increases the expression of proteins in the branched-chain amino acid (BCAA) catabolism pathway. Activity is further augmented through phosphorylation of the enzyme that catalyzes this pathway’s committed step. Conversely, in the liver cancer fibrolamellar carcinoma (FLC)-which we demonstrate to have high mitochondrial calcium levels-expression of BCAA catabolism enzymes is suppressed. We also observe uniporter-dependent suppression of the transcription factor KLF15, a master regulator of liver metabolic gene expression, including those involved in BCAA catabolism. Notably, loss of uniporter activity upregulates KLF15, along with its transcriptional target ornithine transcarbamylase (OTC), a component of the urea cycle, suggesting that uniporter hyperactivation may contribute to the hyperammonemia observed in FLC patients. Collectively, we establish that FLC has increased mitochondrial calcium levels, and identify an important role for mitochondrial calcium signaling in metabolic adaptation through the transcriptional regulation of metabolism.

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Section: Resultsmentioning

confidence: 99%

Mitochondrial Calcium Signaling Regulates Branched-Chain Amino Acid Catabolism in Fibrolamellar Carcinoma

Marsh,

MacEwen,

Chea

et al. 2024

Preprint

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“…Over the past decade, studies have identified KLF15 as a crucial regulator of metabolism [45], showing that KLF15 enhances bile acid production in the liver, leading to increased nutrient uptake [46]. This suggests that KLF15 may emerge as a major therapeutic target for bile-acid-related metabolic diseases [47]. A study implicates HNF4A as the top upstream regulator of metabolism in liver cancer, particularly in a subtype of cholangiocarcinoma with high HNF4A and genes related to bile acid metabolism [48].…”

Section: Discussionmentioning

confidence: 99%

Establishment and Validation of Novel Prognostic Subtypes in Hepatocellular Carcinoma Based on Bile Acid Metabolism Gene Signatures Using Bulk and Single-Cell RNA-Seq Data

Qu,

Gong,

Zhao

et al. 2024

IJMS

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Hepatocellular carcinoma (HCC) is a highly detrimental cancer type and has limited therapeutic options, posing significant threats to human health. The development of HCC has been associated with a disorder in bile acid (BA) metabolism. In this study, we employed an integrative approach, combining various datasets and omics analyses, to comprehensively characterize the tumor microenvironment in HCC based on genes related to BA metabolism. Our analysis resulted in the classification of HCC samples into four subtypes (C1, C2a, C2b, and C3). Notably, subtype C2a, characterized by the highest bile acid metabolism score (BAMS), exhibited the highest survival probability. This subtype also demonstrated increased immune cell infiltration, lower cell cycle scores, reduced AFP levels, and a lower risk of metastasis compared to subtypes C1 and C3. Subtype C1 displayed poorer survival probability and elevated cell cycle scores. Importantly, the identified subtypes based on BAMS showed potential relevance to the gene expression of drug targets in currently approved drugs and those under clinical research. Genes encoding VEGFR (FLT4 and KDR) and MET were elevated in C2, while genes such as TGFBR1, TGFB1, ADORA3, SRC, BRAF, RET, FLT3, KIT, PDGFRA, and PDGFRB were elevated in C1. Additionally, FGFR2 and FGFR3, along with immune target genes including PDCD1 and CTLA4, were higher in C3. This suggests that subtypes C1, C2, and C3 might represent distinct potential candidates for TGFB1 inhibitors, VEGFR inhibitors, and immune checkpoint blockade treatments, respectively. Significantly, both bulk and single-cell transcriptome analyses unveiled a negative correlation between BA metabolism and cell cycle-related pathways. In vitro experiments further confirmed that the treatment of HCC cell lines with BA receptor agonist ursodeoxycholic acid led to the downregulation of the expression of cell cycle-related genes. Our findings suggest a plausible involvement of BA metabolism in liver carcinogenesis, potentially mediated through the regulation of tumor cell cycles and the immune microenvironment. This preliminary understanding lays the groundwork for future investigations to validate and elucidate the specific mechanisms underlying this potential association. Furthermore, this study provides a novel foundation for future precise molecular typing and the design of systemic clinical trials for HCC therapy.

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Dietary pattern and hepatic lipid metabolism

Zou,

Wang

2023

Liver Research

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Krüppel-like factor 15 in liver diseases: Insights into metabolic reprogramming

Cited by 5 publications

References 95 publications

Mitochondrial Calcium Signaling Regulates Branched-Chain Amino Acid Catabolism in Fibrolamellar Carcinoma

Mitochondrial Calcium Signaling Regulates Branched-Chain Amino Acid Catabolism in Fibrolamellar Carcinoma

Establishment and Validation of Novel Prognostic Subtypes in Hepatocellular Carcinoma Based on Bile Acid Metabolism Gene Signatures Using Bulk and Single-Cell RNA-Seq Data

Dietary pattern and hepatic lipid metabolism

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