Carbohydrate-responsive element-binding protein

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ChREBP.png

Carbohydrate-responsive element-binding protein (ChREBP), also known as MLXIPL (MLX interacting protein-like), is a transcription factor that plays a crucial role in converting excess carbohydrates into fat in the liver. ChREBP is a key regulator of glucose metabolism and is involved in the transcriptional activation of various enzymes necessary for the synthesis of fatty acids, triglycerides, and glycogen.

Function[edit | edit source]

ChREBP is activated by high levels of glucose in the body. Upon activation, it moves into the nucleus of liver cells, where it binds to carbohydrate response elements (ChoRE) in the promoter regions of target genes. This binding initiates the transcription of genes involved in the synthesis of fatty acids and triglycerides, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). ChREBP is thus integral to the process of lipogenesis, the conversion of carbohydrates into fat, which is stored in the liver and adipose tissue.

In addition to its role in lipogenesis, ChREBP is involved in the regulation of glycolysis and gluconeogenesis, processes that are essential for maintaining blood glucose levels. It activates the transcription of glucokinase (GCK), an enzyme that facilitates the first step of glycolysis, thereby promoting the conversion of glucose to pyruvate for energy production.

Regulation[edit | edit source]

The activity of ChREBP is regulated by glucose levels. At low glucose concentrations, ChREBP remains in the cytoplasm in an inactive form. When glucose levels increase, ChREBP is modified through glucosylation, which allows it to translocate into the nucleus and bind to DNA to activate gene transcription.

Phosphorylation also plays a role in the regulation of ChREBP. It can be phosphorylated by AMP-activated protein kinase (AMPK), which inhibits its activity. This serves as a mechanism to prevent excessive fat accumulation in the liver, especially during periods of low energy when AMPK activity is high.

Clinical Significance[edit | edit source]

Dysregulation of ChREBP activity has been implicated in the development of metabolic diseases, such as non-alcoholic fatty liver disease (NAFLD), type 2 diabetes, and obesity. Overactivation of ChREBP can lead to excessive fat synthesis and accumulation in the liver, contributing to the development of NAFLD. Furthermore, alterations in ChREBP function can affect glucose metabolism, potentially leading to insulin resistance and type 2 diabetes.

Research Directions[edit | edit source]

Research into ChREBP continues to explore its potential as a therapeutic target for metabolic diseases. Inhibiting ChREBP activity has been suggested as a strategy to reduce lipogenesis and improve liver health in conditions like NAFLD. Conversely, enhancing ChREBP activity could potentially improve glucose utilization and reduce hyperglycemia in diabetes.

See Also[edit | edit source]

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Contributors: Prab R. Tumpati, MD