Impact of PPAR-Alpha Polymorphisms—The Case of Metabolic Disorders and Atherosclerosis
Open accessAbstract
Peroxisome proliferator activated receptor α (PPARα) has the most relevant biological functions among PPARs. Activation by drugs and dietary components lead to major metabolic changes, from reduced triglyceridemia to improvement in the metabolic syndrome. Polymorphisms of PPARα are of interest in order to improve our understanding of metabolic disorders associated with a raised or reduced risk of diseases. PPARα polymorphisms are mainly characterized by two sequence changes, L162V and V227A, with the latter occurring only in Eastern nations, and by numerous SNPs (Single nucleotide polymorphisms) with a less clear biological role. The minor allele of L162V associates with raised total cholesterol, LDL-C (low-density lipoprotein cholesterol), and triglycerides, reduced HDL-C (high-density lipoprotein metabolism), and elevated lipoprotein (a). An increased cardiovascular risk is not clear, whereas a raised risk of diabetes or of liver steatosis are not well supported. The minor allele of the V227A polymorphism is instead linked to a reduction of steatosis and raised γ-glutamyltranspeptidase levels in non-drinking Orientals, the latter being reduced in drinkers. Lastly, the minor allele of rs4353747 is associated with a raised high-altitude appetite loss. These and other associations indicate the predictive potential of PPARα polymorphisms for an improved understanding of human disease, which also explain variability in the clinical response to specific drug treatments or dietary approaches.
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PPAR-α upregulates enzymes involved in ketogenesis, such as HMG-CoA synthase.
“PPAR-α is a transcription factor that upregulates enzymes involved in ketogenesis, such as HMG-CoA synthase.”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [76]
Ketone body production is crucial for energy provision during caloric restriction, reducing glucose demand and muscle breakdown.
“Ketone body production (ketogenesis) is crucial for energy provision during caloric restriction, as it reduces glucose demand and muscle breakdown.”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [76]
This adaptation spares glucose, facilitating sustained fat loss without loss of lean mass.
“This adaptation spares glucose, facilitating sustained fat loss without the loss of lean mass.”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [76]
Individuals with high PPAR-α expression or activity adapt more readily to fat oxidation, entering ketosis more efficiently.
“Individuals with high PPAR-α expression or activity adapt more readily to fat oxidation, entering ketosis more efficiently.”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [76]
Polymorphisms in the PPARA gene can affect the degree of ketogenic adaptation, influencing fat oxidation rates during caloric deficit.
“Polymorphisms in the PPARA gene can affect the degree of ketogenic adaptation, influencing fat oxidation rates during caloric deficit [75,76].”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [76]
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- Authors
- Ruscica, M., Busnelli, M., Runfola, E., Corsini, A., & Sirtori, C. R.
- Affiliations
- University of Milan (IT)
- Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT)
- Corresponding author
- Ruscica, Massimiliano
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2019-09-06
- Volume
- 20
- Issue
- 18
- Pages
- 4378
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC6770475
- OpenAlex
- W2971493174
- Cited by
- 33
- References
- 91
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 6 · 2023: 5 · 2022: 5 · 2021: 4 · 2018: 1
- FWCI
- 0.20
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Fondazione Carlo Sirtori (2019)
- Cariplo Foundation (2015-0552)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
- Keywords
- PPARα, single nucleotide polymorphisms, metabolic disorders, atherosclerosis, metabolic syndrome, triglyceridemia, lipoprotein metabolism, cardiovascular risk, diabetes mellitus, hepatic steatosis, gamma-glutamyltranspeptidase, genetic susceptibility, drug response variability
- MeSH terms
- Alleles, Animals, Diet, Gene Expression Regulation, Genotype, Humans, Lipoproteins, Metabolic Diseases, Amino Acid Substitution, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, PPAR alpha, Atherosclerosis, Genetic Association Studies
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