Regulation of Ketone Body Metabolism and the Role of PPARα

Abstract

Ketogenesis and ketolysis are central metabolic processes activated during the response to fasting. Ketogenesis is regulated in multiple stages, and a nuclear receptor peroxisome proliferator activated receptor α (PPARα) is one of the key transcription factors taking part in this regulation. PPARα is an important element in the metabolic network, where it participates in signaling driven by the main nutrient sensors, such as AMP-activated protein kinase (AMPK), PPARγ coactivator 1α (PGC-1α), and mammalian (mechanistic) target of rapamycin (mTOR) and induces hormonal mediators, such as fibroblast growth factor 21 (FGF21). This work describes the regulation of ketogenesis and ketolysis in normal and malignant cells and briefly summarizes the positive effects of ketone bodies in various neuropathologic conditions.

Keywords: 3-hydroxy-3-methylglytaryl-CoA synthetase 2 (HMGCS2); fasting; fenofibrate; glioma; melanoma; β hydroxybutyrate.

Figure 1

The metabolism of ketone bodies: ketogenesis takes place in hepatocyte mitochondria, whereas ketolysis involves utilization of ketone bodies in the mitochondria of peripheral tissues. ACAT1—acetoacetyl-CoA thiolase, Ac-CoA—acetyl-CoA, AcAc-CoA—acetoacetyl-CoA, BDH—β-hydroxybutyrate dehydrogenase, bHB—β-hydroxybutyrate, CPT1—carnitine palmitoyltransferase 1, HMGCL—HMG-CoA lyase, HMGCS2—HMG-CoA synthetase, MCT1—monocarboxylate transporter 1, SCOT—succinyl-CoA:3-ketocid-CoA transferase, TCA—tricarboxylic acid cycle.

Figure 2

AMPK and mTOR complex 1 (mTORC1) respond to nutrient supply and cellular energy status. AMPK stimulates catabolism and ketogenesis through activation of PPARα and PGC-1α. mTORC1 blocks PPARα and induces anabolic processes, such as protein and lipid biosynthesis. The abbreviations are explained in the text.

Figure 3

Energy substrates for brain during fasting. The values indicate the percentage of energy derived from utilization of each substrate.