Inositol polyphosphate multikinase modulates free fatty acids-induced insulin resistance in primary mouse hepatocytes

Insulin resistance is a critical mediator of the development of nonalcoholic fatty liver disease (NAFLD). An excess influx of fatty acids to the liver is thought to be a pathogenic cause of insulin resistance and the development of NAFLD. Although elevated levels of free fatty acids (FFA) in plasma...

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Published in:Journal of cellular biochemistry 2023-11, Vol.124 (11), p.1695-1704
Main Authors: Jung, Ik-Rak, Ahima, Rexford S, Kim, Sangwon F
Format: Article
Language:English
Subjects:
Acetylcysteine
Acid resistance
AKT protein
Animals
Fatty acids
Fatty Acids, Nonesterified - pharmacology
Fatty liver
Hepatocytes
Hepatocytes - metabolism
Inositol polyphosphate
Inositols
Insulin
Insulin - pharmacology
Insulin Resistance
Kinases
Liver
Liver diseases
Mice
Molecular modelling
Non-alcoholic Fatty Liver Disease
Phosphorylation
Phosphotransferases (Alcohol Group Acceptor) - genetics
Phosphotransferases (Alcohol Group Acceptor) - metabolism
Proteasomes
Proto-Oncogene Proteins c-akt - genetics
Proto-Oncogene Proteins c-akt - metabolism
Therapeutic targets
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Summary:Insulin resistance is a critical mediator of the development of nonalcoholic fatty liver disease (NAFLD). An excess influx of fatty acids to the liver is thought to be a pathogenic cause of insulin resistance and the development of NAFLD. Although elevated levels of free fatty acids (FFA) in plasma contribute to inducing insulin resistance and NAFLD, the molecular mechanism is not completely understood. This study aimed to determine whether inositol polyphosphate multikinase (IPMK), a regulator of insulin signaling, plays any role in FFA-induced insulin resistance in primary hepatocytes. Here, we show that excess FFA decreased IPMK expression, and blockade of IPMK decrease attenuated the FFA-induced suppression of protein kinase B (Akt) phosphorylation in primary mouse hepatocytes (PMH). Moreover, overexpression of IPMK prevented the FFA-induced suppression of Akt phosphorylation by insulin, while knockout of IPMK exacerbated insulin resistance in PMH. In addition, treatment with MG132, a proteasomal inhibitor, inhibits FFA-induced decrease in IPMK expression and Akt phosphorylation in PMH. Furthermore, treatment with the antioxidant N-acetyl cysteine (NAC) significantly attenuated the FFA-induced reduction of IPMK and restored FFA-induced insulin resistance in PMH. In conclusion, our findings suggest that excess FFA reduces IPMK expression and contributes to the FFA-induced decrease in Akt phosphorylation in PMH, leading to insulin resistance. Our study highlights IPMK as a potential therapeutic target for preventing insulin resistance and NAFLD.
ISSN:0730-2312
1097-4644
1097-4644
DOI:10.1002/jcb.30478