From the Guidelines
During a fasting state of over 12 hours without food or water, the liver increases the activity of the enzyme glucose-6-phosphatase to enhance glucose production through gluconeogenesis. This enzyme is crucial for the final step of both gluconeogenesis and glycogenolysis, as it removes the phosphate group from glucose-6-phosphate, allowing free glucose to be released into the bloodstream. Additionally, there is increased activity of phosphoenolpyruvate carboxykinase (PEPCK) and fructose-1,6-bisphosphatase, which are rate-limiting enzymes in the gluconeogenesis pathway. These enzymatic changes are regulated by hormonal shifts during fasting, particularly increased glucagon and decreased insulin levels, as noted in the context of glucose metabolism 1.
The liver's adaptation to maintain blood glucose levels within the normal range when dietary carbohydrates are unavailable is critical, using alternative substrates like amino acids, lactate, and glycerol to synthesize new glucose molecules, thereby preventing hypoglycemia during the extended fasting period. This process is especially relevant after the first 8 to 12 hours of fasting, when hepatic glycogenolysis is depleted and gluconeogenesis becomes the primary mechanism for glucose production 1.
In clinical practice, avoiding prolonged fasting periods, especially in vulnerable populations like those with severe alcoholic steatohepatitis (ASH), is recommended to prevent depletion of glycogen stores and adverse effects on protein metabolism, as suggested by guidelines for clinical nutrition in liver disease 1. However, in the context of a healthy individual undergoing a fasting state of over 12 hours, the enzymatic changes in the liver, including the increased activity of glucose-6-phosphatase, PEPCK, and fructose-1,6-bisphosphatase, are pivotal for maintaining glucose homeostasis.
From the Research
Enzyme Changes in the Liver for Glucose Production
After over 12 hours without food or water, the body enters a fasting state, and the liver plays a crucial role in glucose production through gluconeogenesis. The key enzyme involved in this process is phosphoenolpyruvate carboxykinase (PEPCK).
- PEPCK is a critical enzyme in gluconeogenesis, especially in the liver and kidney, and its enhanced activity leads to increased glucose output 2.
- The PEPCK pathway is more complex than just gluconeogenesis, and its dysregulation may contribute to the development of obesity, cardiac hypertrophy, stroke, and cancer 2.
- PEPCK activity is primarily regulated through hormonal control of gene transcription, and it is also regulated via a cAMP response unit, which includes a cAMP response element and four binding sites for CCAAT/enhancer-binding protein (C/EBP) 3.
- Retinoic acid receptor-related orphan receptor α (RORα) binds to the PEPCK promoter and interacts with C/EBP to synergistically enhance transcription, and suppression of RORα by siRNA significantly decreases PEPCK transcription 3.
- There are two isoforms of PEPCK: PCK1 and PCK2, and they have distinct functions 2.
- The mitochondrial isoform of PEPCK (PEPCK-M) also plays a role in the regulation of hepatic gluconeogenesis, and its silencing lowers plasma glucose, insulin, and triglycerides, and reduces white adipose and hepatic glycogen 4.
Regulation of PEPCK Expression
The expression of PEPCK is regulated by various factors, including:
- Hormonal control of gene transcription 3
- cAMP response unit, which includes a cAMP response element and four binding sites for CCAAT/enhancer-binding protein (C/EBP) 3
- Retinoic acid receptor-related orphan receptor α (RORα) 3
- Epigenetic regulation, transcription regulation, and posttranscription regulation 2
- Dietary and acid-base stimuli 5
Clinical Relevance
The regulation of PEPCK expression and activity has significant clinical implications, including: