Inhibition of MAP4K4 signaling initiates metabolic reprogramming to protect hepatocytes from lipotoxic damage

Anand, Sumit Kumar; Caputo, Mara; Xia, Ying; Cansby, Emmelie; Kumari, Sima; Henricsson, Marcus; Porosk, Rando; Keuenhof, Katharina; Höög, Johanna L.; Nair, Syam; Marschall, Hanns‐Ulrich; Blüher, Matthias; Mahlapuu, Margit

doi:10.1016/j.jlr.2022.100238

Cited by 7 publications

(5 citation statements)

References 65 publications

(92 reference statements)

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“…In our study, it also appeared that targeting MAP4K4 in KPC cells, with the inhibitor PF06260933, also promoted high ERK and AKT phosphorylation levels similar to what we observed in MKPC cells. Our findings are consistent with recent studies showing elevated phosphorylation of ERK [18,20] or AKT in MAP4K4-depleted cells or tissues [15,51]. mTORC1 and mTORC2 signalling has also been linked to promote PDAC onset, progression, and dissemination [39,52,53].…”

supporting

confidence: 93%

Dichotomous role of the serine/threonine kinase MAP4K4 in pancreatic ductal adenocarcinoma onset and metastasis through control of AKT and ERK pathways

Juin,

Spence,

Machesky

2024

The Journal of Pathology

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MAP4K4 is a serine/threonine kinase of the STE20 family involved in the regulation of actin cytoskeleton dynamics and cell motility. It has been proposed as a target of angiogenesis and inhibitors show potential in cardioprotection. MAP4K4 also mediates cell invasion in vitro, is overexpressed in various types of cancer, and is associated with poor patient prognosis. Recently, MAP4K4 has been shown to be overexpressed in pancreatic cancer, but its role in tumour initiation, progression, and metastasis is unknown. Here, using the KrasG12D Trp53R172H Pdx1‐Cre (KPC) mouse model of pancreatic ductal adenocarcinoma (PDAC), we show that deletion of Map4k4 drives tumour initiation and progression. Moreover, we report that the acceleration of tumour onset is also associated with an overactivation of ERK and AKT, two major downstream effectors of KRAS, in vitro and in vivo. In contrast to the accelerated tumour onset caused by loss of MAP4K4, we observed a reduction in metastatic burden with both the KPC model and in an intraperitoneal transplant assay indicating a major role of MAP4K4 in metastatic seeding. In summary, our study sheds light on the dichotomous role of MAP4K4 in the initiation of PDAC onset, progression, and metastatic dissemination. It also identifies MAP4K4 as a possible druggable target against pancreatic cancer spread, but with the caveat that targeting MAP4K4 might accelerate early tumorigenesis. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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supporting

confidence: 93%

Dichotomous role of the serine/threonine kinase MAP4K4 in pancreatic ductal adenocarcinoma onset and metastasis through control of AKT and ERK pathways

Juin,

Spence,

Machesky

2024

The Journal of Pathology

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“…Next, we examined a potential genetic compensation response caused by Taok3 gene knockout, by quantifying the expression of related STE20 kinases which have been previously described to augment the risk of NAFLD development via increased hepatocellular lipotoxicity—TAOK1 (also known as MAP3K16 or PSK2), MST3 (also known as STK24), MST4 (also known as STK26 or MASK), STK25 (also known as YSK1 or SOK1), and MAP4K4 (also known as NIK or HGK) (Cansby et al 2019a , 2019b ; Caputo et al 2021a , 2021b ; Anand et al 2022 ; Amrutkar et al 2016a , 2016b , 2015a , 2015b ; Nerstedt et al 2020 ; Nunez-Duran et al 2018 ; Xia et al 2023 )—in five different organs from high-fat diet-fed Taok3 –/– and wild-type mice. In addition, we compared between the genotypes the transcript levels of TAOK2 (also known as MAP3K17 or PSK1), which together with TAOK1, is the protein displaying the highest similarity with TAOK3.…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, we here only examined in Taok3 –/– mice the expression of a selected portion of the STE20 kinases, which are either most closely related to TAOK3 ( i.e ., GCK-VIII subfamily members TAOK1 and TAOK2) and/or have been previously implicated to increase the risk of NAFLD susceptibility ( i.e ., GCK-III subfamily members MST3, MST4, and STK25, and GCK-IV subfamily member MAP4K4). All these kinases except for TAOK2 have been described as critical mediators of hepatocellular lipotoxic milieu by expression analysis in human liver biopsies, revealing a positive correlation between their transcript levels and the severity of NAFLD, and by in vitro experiments in human hepatocytes, demonstrating that their respective gene silencing protects against ectopic lipid storage and oxidative/ER stress by shifting the metabolic balance from lipid anabolism towards lipid catabolism (Cansby et al 2019a ; Caputo et al 2021a ; Anand et al 2022 ; Amrutkar et al 2016a , 2016b ; Nerstedt et al 2020 ; Xia et al 2023 ). Furthermore, the in vivo inactivation of STK25 and MST3 has been shown to effectively hinder the initiation and aggravation of NAFLD in obese mice, and to dampen the development of diet-induced systemic hyperinsulinemia (Cansby et al 2019b ; Nunez-Duran et al 2018 ; Amrutkar et al 2015a ; Caputo et al 2021b ).…”

Section: Discussionmentioning

confidence: 99%

Knockout of STE20-type kinase TAOK3 does not attenuate diet-induced NAFLD development in mice

Xia,

Andersson,

Caputo

et al. 2023

Mol Med

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Objective Non-alcoholic fatty liver disease (NAFLD), the primary hepatic consequence of obesity, is affecting about 25% of the global adult population. The aim of this study was to examine the in vivo role of STE20-type protein kinase TAOK3, which has been previously reported to regulate hepatocellular lipotoxicity in vitro, in the development of NAFLD and systemic insulin resistance in the context of obesity. Methods Taok3 knockout mice and wild-type littermates were challenged with a high-fat diet. Various in vivo tests were performed to characterize the whole-body metabolism. NAFLD progression in the liver, and lipotoxic damage in adipose tissue, kidney, and skeletal muscle were compared between the genotypes by histological assessment, immunofluorescence microscopy, protein and gene expression profiling, and biochemical assays. Intracellular lipid accumulation and oxidative/ER stress were analyzed in cultured human and mouse hepatocytes where TAOK3 was knocked down by small interfering RNA. The expression of TAOK3-related STE20-type kinases was quantified in different organs from high-fat diet-fed Taok3–/– and wild-type mice. Results TAOK3 deficiency had no impact on body weight or composition, food consumption, locomotor activity, or systemic glucose or insulin homeostasis in obese mice. Consistently, Taok3–/– mice and wild-type littermates developed a similar degree of high-fat diet-induced liver steatosis, inflammation, and fibrosis, and we detected no difference in lipotoxic damage of adipose tissue, kidney, or skeletal muscle when comparing the two genotypes. In contrast, the silencing of TAOK3 in vitro markedly suppressed ectopic lipid accumulation and metabolic stress in mouse and human hepatocytes. Interestingly, the hepatic mRNA abundance of several TAOK3-related kinases, which have been previously implicated to increase the risk of NAFLD susceptibility, was significantly elevated in Taok3–/–vs. wild-type mice. Conclusions In contrast to the in vitro observations, genetic deficiency of TAOK3 in mice failed to mitigate the detrimental metabolic consequences of chronic exposure to dietary lipids, which may be partly attributable to the activation of liver-specific compensation response for the genetic loss of TAOK3 by related STE20-type kinases. Graphical Abstract

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“…To this end, different STE20 family proteins have recently been implicated in exacerbating the risk of MASLD in the context of obesity. Similarly to MST4 [18], STK25 and MST3 (comprising the GCK-III subfamily of STE20 kinases together with MST4), MAP4K4 (belonging to the GCK-IV subfamily), as well as TAOK1 and TAOK3 (GCK-VIII subfamily members) have been identified as important drivers of hepatocellular lipotoxicity based on expression profiling in human liver biopsies, which demonstrates that their mRNA abundance is positively correlated with the key histological features of MASLD, and via in vitro investigations in cultured hepatocytes, which reveal that the knockdown of their respective genes alleviates fat accumulation by causing a shift from lipid anabolism towards catabolism [18,[36][37][38][39][40][41]. We and other research groups also found that the inactivation of STK25 or MST3 in mice, either by genetic knockout or treatment with antisense oligonucleotides, improves whole-body insulin sensitivity and effectively ameliorates the full spectrum of diet-induced MASLD encompassing suppressed hepatic steatosis, inflammation, and fibrosis [36,[42][43][44].…”

Section: Discussionmentioning

confidence: 99%

Genetic Ablation of STE20-Type Kinase MST4 Does Not Alleviate Diet-Induced MASLD Susceptibility in Mice

Caputo,

Andersson,

Xia

et al. 2024

IJMS

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Metabolic dysfunction-associated steatotic liver disease (MASLD) and its advanced subtype, metabolic dysfunction-associated steatohepatitis (MASH), have emerged as the most common chronic liver disease worldwide, yet there is no targeted pharmacotherapy presently available. This study aimed to investigate the possible in vivo function of STE20-type protein kinase MST4, which was earlier implicated in the regulation of hepatocellular lipotoxic milieu in vitro, in the control of the diet-induced impairment of systemic glucose and insulin homeostasis as well as MASLD susceptibility. Whole-body and liver-specific Mst4 knockout mice were generated by crossbreeding conditional Mst4fl/fl mice with mice expressing Cre recombinase under the Sox2 or Alb promoters, respectively. To replicate the environment in high-risk subjects, Mst4–/– mice and their wild-type littermates were fed a high-fat or a methionine–choline-deficient (MCD) diet. Different in vivo tests were conducted in obese mice to describe the whole-body metabolism. MASLD progression in the liver and lipotoxic damage to adipose tissue, kidney, and skeletal muscle were analyzed by histological and immunofluorescence analysis, biochemical assays, and protein and gene expression profiling. In parallel, intracellular fat storage and oxidative stress were assessed in primary mouse hepatocytes, where MST4 was silenced by small interfering RNA. We found that global MST4 depletion had no effect on body weight or composition, locomotor activity, whole-body glucose tolerance or insulin sensitivity in obese mice. Furthermore, we observed no alterations in lipotoxic injuries to the liver, adipose, kidney, or skeletal muscle tissue in high-fat diet-fed whole-body Mst4–/– vs. wild-type mice. Liver-specific Mst4–/– mice and wild-type littermates displayed a similar severity of MASLD when subjected to an MCD diet, as evidenced by equal levels of steatosis, inflammation, hepatic stellate cell activation, fibrosis, oxidative/ER stress, and apoptosis in the liver. In contrast, the in vitro silencing of MST4 effectively protected primary mouse hepatocytes against ectopic lipid accumulation and oxidative cell injury triggered by exposure to fatty acids. In summary, these results suggest that the genetic ablation of MST4 in mice does not mitigate the initiation or progression of MASLD and has no effect on systemic glucose or insulin homeostasis in the context of nutritional stress. The functional compensation for the genetic loss of MST4 by yet undefined mechanisms may contribute to the apparent discrepancy between in vivo and in vitro phenotypic consequences of MST4 silencing.

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Inhibition of MAP4K4 signaling initiates metabolic reprogramming to protect hepatocytes from lipotoxic damage

Cited by 7 publications

References 65 publications

Dichotomous role of the serine/threonine kinase MAP4K4 in pancreatic ductal adenocarcinoma onset and metastasis through control of AKT and ERK pathways

Dichotomous role of the serine/threonine kinase MAP4K4 in pancreatic ductal adenocarcinoma onset and metastasis through control of AKT and ERK pathways

Knockout of STE20-type kinase TAOK3 does not attenuate diet-induced NAFLD development in mice

Genetic Ablation of STE20-Type Kinase MST4 Does Not Alleviate Diet-Induced MASLD Susceptibility in Mice

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