Event: 861

Key Event Title


Decreased, Ketogenesis (production of ketone bodies)

Short name


Decreased, Ketogenesis (production of ketone bodies)

Biological Context


Level of Biological Organization

Cell term


Cell term
eukaryotic cell

Organ term


Key Event Components


Process Object Action
ketosis decreased

Key Event Overview

AOPs Including This Key Event


AOP Name Role of event in AOP
PPARα antagonism leading to body-weight loss KeyEvent



Taxonomic Applicability


Term Scientific Term Evidence Link
Mus musculus Mus musculus High NCBI
Homo sapiens Homo sapiens High NCBI

Life Stages


Life stage Evidence
Not Otherwise Specified Not Specified
Adults High

Sex Applicability


Term Evidence
Male High
Female High

Key Event Description


PPARα acts as a transcriptional activator for many of the genes involved in ketogenesis (Desvergne and Wahili 1999, Kersten 2014).  Thus, decreased PPARα nuclear signaling results in decreased transcriptional expression of genes that are regulated by PPARα, and subsequently, decreased expression of the coded proteins and enzymes that ultimately impair ketogenesis.  Ketogenesis is critical to supporting general systemic energy homeostasis in fasting events (Cahill 2006, Evans et al 2004, Sengupta et al 2010), thus KE4 becomes important after short term energy stores (glycogen) become limited (Muoio et al 2002).  Le May et al (2000) have shown decreased ketogenesis  in livers of PPAR null mice linked to impaired mitochondrial hydroxymethylglutaryl-CoA synthase (Hmgcs) gene expression.

Genes Involved:  Not only does PPARα regulate the genes that catalyze the upstream production of the raw materials utilized in ketogenesis through fatty acid beta-oxidation (see decreased peroxisomal (KE3) and mitochondrial (KE4) fatty acid beta oxidation, upstream), but also directly induces key enzymes in the ketogenesis pathway including 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2 (Hmgcs2), 3-hydroxy-3-methylglutaryl-CoA lyase (Hmgcl), and acetyl-CoA acetyltransferase 1 (Acat1, Kersten et al 2014, Le May et al 2000). PPARα is recognized as the master transcriptional activator of ketogenic genes (Sengupta et al 2010, Desvergne and Wahli 1999).


Metabolism Affected:  The liver plays a key role in processing the fundamental energy substrate, acetyl-CoA, into metabolic currencies that contribute to the systemic cellular energy needs of the whole organism.  The liver represents a key organ involved in systemic energy distribution given its ability to synthesize glucose (an ability shared only with the kidney, Gerich et al 2001) as well as its exclusive role in the generation of ketone bodies (Cahill 2006, Sengupta et al 2010, Kersten 2014).  This is especially important for the metabolic energy needs of the brain which can only use glucose and the ketone body, β-hydroxybutyrate for cellular energy production (Cahill 2006, Owen 2005, Kersten 2014).  Therefore, ketogenesis is critical to supporting general systemic energy homeostasis in fasting events (Cahill 2006, Evans et al 2004, Sengupta et al 2010).  Interference with ketogenesis, for example by PPARα inhibition, has been demonstrated to inhibit β-hydroxybutyrate production (measured in serum) during fasting events in mice (Le May et al 2000, Badman et al 2007, Potthoff 2009, Sengupta et al 2010) and cause hypoketonemia (Muoio et al 2002).  The Badman et al (2007) study indicated that metabolism of fatty acid substrates (measured as liver triglycerides) that would otherwise contribute to β-hydroxybutyrate production was additionally inhibited under PPARα knockout.  

In a fasting state, humans transition from the use of exogenous glucose to glucose derived from glycogen within 4 hours with a steadily increasing proportion of glucose usage that is derived from gluconeogenesis up to 2 days (Cahill 2006).  Beyond 2 days of fasting, ketone body production (β-hydroxybutyrate) increasingly supports the energy demands of the brain (Cahill 2006). 

How It Is Measured or Detected


Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

The quantification of β-hydroxybutyrate described in Cahill 2006 was measured in a cell-free system catalyzed by D(-)-p-hydroxybutyric dehydrogenase where all components of the reaction [ D(-)-fl-hydroxybutyrate + diphosphopyridine nucleotide + = acetoacetate + reduced diphosphopyridine nucleotide + H+ ] were able to be quantitatively determined (Williamson et al 1962).  Serum β-hydroxybutyrate was measured using Stanbio Laboratory small-scale enzymatic assays in Badman et al (2007) and by Wako Chemicals D-3-hydroxybutyric acid kit in Potthoff et al (2009).  SMART micro-FPLC (Amersham Biosciences) consisting of a Superose 6 PC 3.2/30 column (Amersham Biosciences) equilibrated in PBS buffer was conducted where triglyceride and cholesterol fractions were investigated by enzymatic assay (Wako Diagnostics) as described in Badman et al (2007). Clinical observations of ketone bodies have been simplified by the development of urine test strips that can provide quantitative values for the ketone bodies aceto-acetate, acetone and 3-hydroxybutyrate using reflectometry (Penders et al 2005).  In Le May et al (2000), glucose, L-hydroxybutyrate and acetoacetate concentrations were measured in the neutralized perchloric filtrates by enzymatic methods.  In Muoio et al (2002), β-hydroxybutyrate was measured in blood serum comparing wild type and PPARα knockout mice.

Domain of Applicability


Evidence was provided for human in Cahill (2006), Owen et al (2005) and Williamson et al (1962).  Evidence for mouse was provided in Kersten et al (1999).  Comparative investigations of ketone body formation comparing human and mouse is not well established relative to fatty-acid oxidation comparisons.

Evidence for Perturbation by Stressor



Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E: Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell metabolism 2007, 5(6):426-437.


Cahill Jr., G.F., 2006. Fuel metabolism in starvation. Annual Review of Nutrition 26:1e22.


Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocrine Reviews 20(5): 649-688.


Evans RM, Barish GD, Wang YX: PPARs and the complex journey to obesity. Nat Med 2004, 10(4):355-361.


Gerich JE, Meyer C, Woerle HJ, Stumvoll M: Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care 2001, 24(2):382-391.


Kersten S.  2014. Integrated physiology and systems biology of PPARalpha. Molecular Metabolism 2014, 3(4):354-371.


Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W: Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest 1999, 103(11):1489-1498.


Le May et al., 2000. Reduced hepatic fatty acid oxidation in fasting PPARK null mice is due to impaired mitochondrial hydroxymethylglutaryl-CoA synthase gene expression. FEBS Lett. 475: 163-166.


Muoio, D.M., MacLean, P.S., Lang, D.B., Li, S., Houmard, J.A., Way, J.M., Winegar, D.A., Corton, J.C., Dohm, G.L., Kraus, W.E., 2002. Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) alpha knock-out mice. Evidence for compensatory regulation by PPAR delta. J. Biol. Chem. 277, 26089-26097.


Owen OE: Ketone bodies as a fuel for the brain during starvation. Biochem Mol Biol Educ 2005, 33(4):246-251.


Penders J, Fiers T, Giri M, Wuyts B, Ysewyn L, Delanghe JR: Quantitative measurement of ketone bodies in urine using reflectometry. Clin Chem Lab Med 2005, 43(7):724-729.


Potthoff MJ, Inagaki T, Satapati S, Ding X, He T, Goetz R, Mohammadi M, Finck BN, Mangelsdorf DJ,


Kliewer SA et al: FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proceedings of the National Academy of Sciences 2009, 106(26):10853-10858.


Sengupta S, Peterson TR, Laplante M, Oh S, Sabatini DM: mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 2010, 468(7327):1100-1104.


Williamson DH, Mellanby J, Krebs HA: Enzymic determination of d(−)-β-hydroxybutyric acid and acetoacetic acid in blood. Biochem J 1962, 82(1):90-96.