Impact of PPAR-Alpha Polymorphisms—The Case of Metabolic Disorders and Atherosclerosis

Abstract

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.

Discovery of a Carbamoyl Phosphate Synthetase 1–Deficient HCC Subtype With Therapeutic Potential Through Integrative Genomic and Experimental Analysis

“…( 33 ) PPARα can not only regulate lipid metabolism but also be activated by adipose tissue‐derived fatty acids. ( 37 ) Aberrant PPARα activation or inhibition can also lead to other metabolic diseases apart from cancer. Komatsu et al reported that PPARα is down‐regulated, not activated, in one of the UCDs called adult‐onset type II citrullinemia, which is frequently accompanied by hyperammonemia and hepatic steatosis.…”

The contribution of the AGT, GNB3, MTHFR, MTRR, ApoE, and PPARα polymorphisms to the development of masked arterial hypertension in patients with low and moderate cardiovascular risk

“…Имеются данные о том, что полиморфизм G/C rs4253778 гена PPARα ассоциирован с дислипидемией и, соответственно, может влиять на развитие атеросклероза и уровень АД [20]. В связи с этим было логично предположить возможное опосредованное влияние полиморфизма данного гена на развитие МАГ.…”

“…Однако в нашей работе не выявлено связи между частотой встречаемости полиморфизма гена PPARα и развитием МАГ. По данным литературы, полиморфизм PPARα может быть в большей степени связан с повышением уровня глюкозы и развитием сахарного диабета [20]. Ряд исследований описывают связь полиморфизма PPARα с риском развития дислипидемии и ишемической болезни сердца, а не АГ, у больных с высоким ССР [20].…”

Quercetin as a protective agent for liver diseases: A comprehensive descriptive review of the molecular mechanism

“…PPARα (NR1C1) is abundant in the liver and is the main nuclear receptor for fatty acid β‐oxidation (Y. Wang, Nakajima, Gonzalez, & Tanaka, 2020). In WAT, PPARα induces the expression of mitochondrial acyl coenzyme A (CoA) dehydrogenase upon activation by browning, thereby stimulating the transcription of the hepatic fatty acid transporter protein to reduce plasma TG and low‐density lipoprotein cholesterol (LDL‐C) levels and increase HDL‐C and directly or indirectly involved in UCP1 expression (Ruscica, Busnelli, Runfola, Corsini, & Sirtori, 2019). In BAT, PPARα acts synergistically with PGC1α to stimulate lipid oxidation as well as thermogenesis (Padovano, Podrini, Boletta, & Caplan, 2018).…”