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.

Pan-Cancer Analysis of Glycolytic and Ketone Bodies Metabolic Genes: Implications for Response to Ketogenic Dietary Therapy

“…A weak negative correlation was observed between glycolysis and KBM ( Figure S2A ). Besides, KBM was highly expressed in normal liver and kidney tissue, which is consistent with the finding that KBM primarily takes place in the liver and kidney ( 33 ). Associations with patient outcomes were examined for every cancer type individually.…”

Pan-Cancer Analysis of Glycolytic and Ketone Bodies Metabolic Genes: Implications for Response to Ketogenic Dietary Therapy

“…A weak negative correlation was observed between glycolysis and KBM ( Figure S2A ). Besides, KBM was highly expressed in normal liver and kidney tissue, which is consistent with the finding that KBM primarily takes place in the liver and kidney ( 33 ). Associations with patient outcomes were examined for every cancer type individually.…”

Glucose and Fatty Acid Metabolism of Dairy Cows in a Total Mixed Ration or Pasture-Based System During Lactation

“…In this sense, we observed AMPK activation was increased during early lactation when levels of NEFA, BHB, and liver triglycerides were elevated compared to late lactation, this is in accordance with other authors that have found an increase in AMPK phosphorylation in bovine hepatocytes treated with increasing doses of BHB and acetic acid (Li et al, 2013;Deng et al, 2015). Also, AMPK has been reported to increase the expression of PPARA which in turn upregulates the expression of lipid oxidation genes CPT1A, HMGCS2, FABP1 (Guzmán et al, 2013;Khan et al, 2014;Grabacka et al, 2016;Li et al, 2020). In fact, we found a positive correlation between the pAMPK to AMPK ratio and mRNA HMGCS2 expression.…”

Dietary citrate supplementation enhances longevity, metabolic health, and memory performance through promoting ketogenesis

“…These results are consistent with previous reports that AMPK is activated in response to a lower energy level and that it blocks anabolic processes by antagonizing TOR signaling (Grabacka et al, 2016).…”

“…We found that 0.1% citrate supplementation for 10 days induced lower levels for all these measurements in w 1118 flies compared to the vehicle groups, indicating reduced energy status in citrate-treated flies (Figure 2a-c). In order to confirm these observations, we also performed Western blots to measure the protein phosphorylation of AMPK and S6 Kinase in flies, as phosphorylation levels of these proteins reflect the relative activity of AMPK and TOR in the energysensing and metabolic pathways (Grabacka et al, 2016). We found that 10 days of citrate supplementation induced increased AMPK activity, but reduced TOR activity in flies, further supporting our observations of reduced energy status in citrate-treated flies (Figure 2d).…”

Pan-Cancer Analysis of Glycolytic and Ketone Bodies Metabolic Genes: Implications for Response to Ketogenic Dietary Therapy

“…A weak negative correlation was observed between glycolysis and KBM ( Figure S2A ). Besides, KBM was highly expressed in normal liver and kidney tissue, which is consistent with the finding that KBM primarily takes place in the liver and kidney ( 33 ). Associations with patient outcomes were examined for every cancer type individually.…”

Glucose and Fatty Acid Metabolism of Dairy Cows in a Total Mixed Ration or Pasture-Based System During Lactation

“…In this sense, we observed AMPK activation was increased during early lactation when levels of NEFA, BHB, and liver triglycerides were elevated compared to late lactation, this is in accordance with other authors that have found an increase in AMPK phosphorylation in bovine hepatocytes treated with increasing doses of BHB and acetic acid (Li et al, 2013;Deng et al, 2015). Also, AMPK has been reported to increase the expression of PPARA which in turn upregulates the expression of lipid oxidation genes CPT1A, HMGCS2, FABP1 (Guzmán et al, 2013;Khan et al, 2014;Grabacka et al, 2016;Li et al, 2020). In fact, we found a positive correlation between the pAMPK to AMPK ratio and mRNA HMGCS2 expression.…”

Dietary citrate supplementation enhances longevity, metabolic health, and memory performance through promoting ketogenesis

“…These results are consistent with previous reports that AMPK is activated in response to a lower energy level and that it blocks anabolic processes by antagonizing TOR signaling (Grabacka et al, 2016).…”

“…We found that 0.1% citrate supplementation for 10 days induced lower levels for all these measurements in w 1118 flies compared to the vehicle groups, indicating reduced energy status in citrate-treated flies (Figure 2a-c). In order to confirm these observations, we also performed Western blots to measure the protein phosphorylation of AMPK and S6 Kinase in flies, as phosphorylation levels of these proteins reflect the relative activity of AMPK and TOR in the energysensing and metabolic pathways (Grabacka et al, 2016). We found that 10 days of citrate supplementation induced increased AMPK activity, but reduced TOR activity in flies, further supporting our observations of reduced energy status in citrate-treated flies (Figure 2d).…”

Pan-Cancer Analysis of Glycolytic and Ketone Bodies Metabolic Genes: Implications for Response to Ketogenic Dietary Therapy

“…A weak negative correlation was observed between glycolysis and KBM ( Figure S2A ). Besides, KBM was highly expressed in normal liver and kidney tissue, which is consistent with the finding that KBM primarily takes place in the liver and kidney ( 33 ). Associations with patient outcomes were examined for every cancer type individually.…”

Glucose and Fatty Acid Metabolism of Dairy Cows in a Total Mixed Ration or Pasture-Based System During Lactation

“…In this sense, we observed AMPK activation was increased during early lactation when levels of NEFA, BHB, and liver triglycerides were elevated compared to late lactation, this is in accordance with other authors that have found an increase in AMPK phosphorylation in bovine hepatocytes treated with increasing doses of BHB and acetic acid (Li et al, 2013;Deng et al, 2015). Also, AMPK has been reported to increase the expression of PPARA which in turn upregulates the expression of lipid oxidation genes CPT1A, HMGCS2, FABP1 (Guzmán et al, 2013;Khan et al, 2014;Grabacka et al, 2016;Li et al, 2020). In fact, we found a positive correlation between the pAMPK to AMPK ratio and mRNA HMGCS2 expression.…”

Dietary citrate supplementation enhances longevity, metabolic health, and memory performance through promoting ketogenesis

“…These results are consistent with previous reports that AMPK is activated in response to a lower energy level and that it blocks anabolic processes by antagonizing TOR signaling (Grabacka et al, 2016).…”

“…We found that 0.1% citrate supplementation for 10 days induced lower levels for all these measurements in w 1118 flies compared to the vehicle groups, indicating reduced energy status in citrate-treated flies (Figure 2a-c). In order to confirm these observations, we also performed Western blots to measure the protein phosphorylation of AMPK and S6 Kinase in flies, as phosphorylation levels of these proteins reflect the relative activity of AMPK and TOR in the energysensing and metabolic pathways (Grabacka et al, 2016). We found that 10 days of citrate supplementation induced increased AMPK activity, but reduced TOR activity in flies, further supporting our observations of reduced energy status in citrate-treated flies (Figure 2d).…”