Dataset Information

Elimination of Age-Associated Hepatic Steatosis and Correction of Aging Phenotype by Inhibition of cdk4-C/EBPα-p300 Axis.

ABSTRACT: The aging liver is affected by several disorders, including steatosis, that can lead to a decline of liver functions. Here, we present evidence that the cdk4-C/EBPα-p300 axis is a critical regulator of age-associated disorders, including steatosis. We found that patients with non-alcoholic fatty liver disease (NAFLD) have increased levels of cdk4 and that cdk4-resistant C/EBPα-S193A mice do not develop hepatic steatosis with advancing age. Underlying mechanisms include a block in C/EBPα activation and subsequent failure in activation of enzymes involved in the development of NAFLD. Inhibition of cdk4 in aged wild-type (WT) mice by a specific cdk4 inhibitor, PD-0332991, reduces C/EBPα-p300 complexes and eliminates hepatic steatosis. Moreover, the inhibition of cdk4 in aged mice reverses many age-related disorders. Mechanisms of correction include elimination of cellular senescence and alterations in the chromatin structure of hepatocytes. Thus, the inhibition of cdk4 might be considered as a therapeutic approach to correct age-associated liver disorders.

SUBMITTER: Nguyen P

PROVIDER: S-EPMC8209958 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Publications

Elimination of Age-Associated Hepatic Steatosis and Correction of Aging Phenotype by Inhibition of cdk4-C/EBPα-p300 Axis.

Nguyen Phuong P Valanejad Leila L Cast Ashley A Wright Mary M Garcia Jose M JM El-Serag Hashem B HB Karns Rebekah R Timchenko Nikolai A NA

Cell reports 20180801 6

The aging liver is affected by several disorders, including steatosis, that can lead to a decline of liver functions. Here, we present evidence that the cdk4-C/EBPα-p300 axis is a critical regulator of age-associated disorders, including steatosis. We found that patients with non-alcoholic fatty liver disease (NAFLD) have increased levels of cdk4 and that cdk4-resistant C/EBPα-S193A mice do not develop hepatic steatosis with advancing age. Underlying mechanisms include a block in C/EBPα activati ...[more]

PMID: 30089269

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Project description:Background and Objectives: Metabolic-dysfunction-associated steatotic liver disease or MASLD is the main cause of chronic liver diseases in children, and it is estimated to affect 35% of children living with obesity. This study aimed to identify metabolic phenotypes associated with two advanced stages of MASLD (hepatic steatosis and hepatic steatosis plus fibrosis) in Mexican children with obesity. Materials and Methods: This is a cross-sectional analysis derived from a randomized clinical trial conducted in children and adolescents with obesity aged 8 to 16 years. Anthropometric and biochemical data were measured, and targeted metabolomic analyses were carried out using mass spectrometry. Liver steatosis and fibrosis were estimated using transient elastography (Fibroscan® Echosens, Paris, France). Three groups were studied: a non-MASLD group, an MASLD group, and a group for MASLD + fibrosis. A partial least squares discriminant analysis (PLS-DA) was performed to identify the discrimination between the study groups and to visualize the differences between their heatmaps; also, Variable Importance Projection (VIP) plots were graphed. A VIP score of >1.5 was considered to establish the importance of metabolites and biochemical parameters that characterized each group. Logistic regression models were constructed considering VIP scores of >1.5, and the receiver operating characteristic (ROC) curves were estimated to evaluate different combinations of variables. Results: The metabolic MASLD phenotype was associated with increased concentrations of ALT and decreased arginine, glycine, and acylcarnitine (AC) AC5:1, while MASLD + fibrosis, an advanced stage of MASLD, was associated with a phenotype characterized by increased concentrations of ALT, proline, and alanine and a decreased Matsuda Index. Conclusions: The metabolic MASLD phenotype changes as this metabolic dysfunction progresses. Understanding metabolic disturbances in MASLD would allow for early identification and the development of intervention strategies focused on limiting the progression of liver damage in children and adolescents.

Dataset Information

Elimination of Age-Associated Hepatic Steatosis and Correction of Aging Phenotype by Inhibition of cdk4-C/EBPα-p300 Axis.

Publications

Elimination of Age-Associated Hepatic Steatosis and Correction of Aging Phenotype by Inhibition of cdk4-C/EBPα-p300 Axis.

Similar Datasets

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