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GPAT1 Activity and Abundant Palmitic Acid Impair Insulin Suppression of Hepatic Glucose Production in Primary Mouse Hepatocytes.
Zhang, Chongben; Steadman, Mathew; Santos, Hudson P; Shaikh, Saame R; Xavier, Rose Mary.
Afiliação
  • Zhang C; Biobehavioral Laboratory, School of Nursing, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. Electronic address: zcb@email.unc.edu.
  • Steadman M; Biobehavioral Laboratory, School of Nursing, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
  • Santos HP; School of Nursing and Health Studies, University of Miami, Coral Gables, FL, United States.
  • Shaikh SR; Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
  • Xavier RM; Biobehavioral Laboratory, School of Nursing, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. Electronic address: rxavier@email.unc.edu.
J Nutr ; 154(4): 1109-1118, 2024 04.
Article em En | MEDLINE | ID: mdl-38354952
ABSTRACT

BACKGROUND:

Glycerol-3-phosphate acyltransferase (GPAT) activity is correlated with obesity and insulin resistance in mice and humans. However, insulin resistance exists in people with normal body weight, and individuals with obesity may be metabolically healthy, implying the presence of complex pathophysiologic mechanisms underpinning insulin resistance.

OBJECTIVE:

We asked what conditions related to GPAT1 must be met concurrently for hepatic insulin resistance to occur.

METHODS:

Mouse hepatocytes were overexpressed with GPATs via adenoviral infection or exposed to high or low concentrations of glucose. Glucose production by the cells and phosphatidic acid (PA) content in the cells were assayed, GPAT activity was measured, relative messenger RNA expressions of sterol-regulatory element-binding protein 1c (SREBP1c), carbohydrate response element-binding protein (ChREBP), and GPAT1 were analyzed, and insulin signaling transduction was examined.

RESULTS:

Overexpressing GPAT1 in mouse hepatocytes impaired insulin's suppression of glucose production, together with an increase in both N-ethylmaleimide-resistant GPAT activity and the content of di-160 PA. Akt-mediated insulin signaling was inhibited in hepatocytes that overexpressed GPAT1. When the cells were exposed to high-glucose concentrations, insulin suppression of glucose production was impaired, and adding palmitic acid exacerbated this impairment. High-glucose exposure increased the expression of SREBP1c, ChREBP, and GPAT1 by ∼2-, 5-, and 5.7-fold, respectively. The addition of 200 mM palmitic acid or linoleic acid to the culture media did not change the upregulation of expression of these genes by high glucose. High-glucose exposure increased di-160 PA content in the cells, and adding palmitic acid further increased di-160 PA content. The effect was specific to palmitic acid because linoleic acid did not show these effects.

CONCLUSION:

These data demonstrate that high-GPAT1 activity, whether induced by glucose exposure or acquired by transfection, and abundant palmitic acid can impair insulin's ability to suppress hepatic glucose production in primary mouse hepatocytes.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Resistência à Insulina / Insulina Limite: Animals Idioma: En Revista: J Nutr Ano de publicação: 2024 Tipo de documento: Article País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Resistência à Insulina / Insulina Limite: Animals Idioma: En Revista: J Nutr Ano de publicação: 2024 Tipo de documento: Article País de publicação: Estados Unidos