What metabolic pathway modulation promotes high rates of ketone synthesis in a fasting liver, specifically through inhibiting cholesterol synthesis, decreasing glycolysis, increasing fatty acid oxidation, decreasing gluconeogenesis, or decreasing ketone utilization by the liver?

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Dainyal Siddiqui, MD

Internal Medicine

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Manuel Jimenez, MD

Cardiology

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Franz Pierre-Louis, MD

Infectious Disease

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Last updated: May 6, 2025 • View editorial policy

From the Guidelines

In a fasting liver, high rates of ketone synthesis would be promoted by excessive increasing fatty acid oxidation. This process is mediated by the nuclear receptor peroxisome proliferator-activated receptor α (PPARα), a central transcriptional factor regulating fatty acid metabolism, including fatty acid oxidation, transport, and ketogenesis, which is upregulated during fasting or ketogenic states 1. Key points to consider include:

  • The liver's shift to using fatty acids as its primary fuel source during fasting, involving the breakdown of stored triglycerides into fatty acids that undergo beta-oxidation in the mitochondria.
  • The production of large amounts of acetyl-CoA from increased fatty acid oxidation, which exceeds the capacity of the TCA cycle and is diverted toward ketogenesis.
  • The crucial role of PPARα in regulating this metabolic adaptation, which is essential for preserving glucose for tissues that absolutely require it while providing an alternative energy source for others. The induction of the PPARα pathway may serve as an additional explanation of the beneficial effects of ketogenic diets or intermittent calorie restriction, particularly in the context of impaired PPAR-signalling in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) 1.

From the Research

Metabolic Pathways and Ketone Synthesis

In a fasting liver, high rates of ketone synthesis would be promoted by modulation of the following metabolic pathways:

  • Excessive increasing fatty acid oxidation: This is supported by the study 2, which states that fasting causes substantial metabolic adaptations in the liver, including the stimulation of fatty acid oxidation and ketogenesis.
  • Decreasing ketone utilization by the liver: According to the study 3, endogenous β-OH butyrate signaling transcriptionally regulates hepatic fatty acid oxidation and ketogenesis, and β-OH butyrate produced by the liver feeds back to inhibit hepatic β-oxidation and ketogenesis during fasting.

Inhibition of Other Pathways

The following pathways do not directly promote high rates of ketone synthesis:

  • Inhibiting of cholesterol synthesis: There is no direct evidence in the provided studies to support the inhibition of cholesterol synthesis as a promoter of ketone synthesis.
  • Decreasing glycolysis: While glycolysis is decreased during fasting, there is no direct evidence to suggest that this decrease promotes ketone synthesis.
  • Decreased gluconeogenesis: According to the study 4, impaired ketogenesis is associated with increased gluconeogenesis, but decreased gluconeogenesis does not directly promote ketone synthesis.

Regulation of Ketogenesis

Ketogenesis is regulated by various factors, including:

  • Hormonal changes: The study 2 states that the induction of fatty acid oxidation and ketogenesis during fasting is mainly driven by interrelated changes in plasma levels of various hormones.
  • Plasma nonesterified fatty acid (NEFA) levels: The study 2 also states that the increase in plasma NEFA levels mediates the transcriptional regulation of ketogenesis.
  • Peroxisome proliferator-activated receptor (PPAR)α: The study 2 mentions that PPARα, supported by CREB3L3, mediates the transcriptional regulation of ketogenesis.

References

2
Research

Mechanisms of hepatic fatty acid oxidation and ketogenesis during fasting.

Trends in endocrinology and metabolism: TEM, 2024

3
Research

Role of ketone signaling in the hepatic response to fasting.

American journal of physiology. Gastrointestinal and liver physiology, 2019

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This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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