Ppara, also known as peroxisome proliferator-activated receptor alpha, is a ligand-activated transcription factor. It is a key mediator of lipid metabolism, regulating genes involved in fatty acid transport, catabolism, and oxidation [3,4]. Ppara is also associated with metabolic stress, autophagy, and inflammation pathways, and is of great biological importance in maintaining metabolic homeostasis. Genetic models, such as KO/CKO mouse models, are valuable tools for studying Ppara's functions.

In a murine model of Alzheimer disease, pharmacological activation of Ppara by agonists decreased amyloid pathology, reversed memory deficits, and reduced Aβ levels, indicating its role in regulating autophagy for Aβ clearance [1]. In non-alcoholic fatty liver disease (NAFLD), MIR20B was found to specifically target Ppara, and its overexpression increased hepatic lipid accumulation, while Ppara agonist fenofibrate's effect was suppressed by Mir20b [2]. In mouse liver, Ppara ligand WY14643 activated Cbfa2t3 expression, and Cbfa2t3-/-mice showed increased insulin resistance and lipid accumulation, suggesting Cbfa2t3 is a Ppara-sensitive gene modulating metabolic stress [3]. Intestinal Ppara disruption in mice fed a high-fat diet decreased obesity-associated metabolic disorders and non-alcoholic steatohepatitis (NASH), indicating its role in NASH progression through regulating fatty acid uptake [4].

In conclusion, Ppara plays essential roles in lipid metabolism, autophagy, and metabolic stress. Studies using KO/CKO mouse models have revealed its significance in diseases like Alzheimer disease, NAFLD, and NASH, providing insights into potential therapeutic strategies for these conditions.

References:

1. Luo, Rongcan, Su, Ling-Yan, Li, Guiyu, Li, Jiali, Yao, Yong-Gang. 2019. Activation of PPARA-mediated autophagy reduces Alzheimer disease-like pathology and cognitive decline in a murine model. In Autophagy, 16, 52-69. doi:10.1080/15548627.2019.1596488. https://pubmed.ncbi.nlm.nih.gov/30898012/

2. Lee, Yo Han, Jang, Hyun-Jun, Kim, Sounkou, Nam, Dougu, Choi, Jang Hyun. 2021. Hepatic MIR20B promotes nonalcoholic fatty liver disease by suppressing PPARA. In eLife, 10, . doi:10.7554/eLife.70472. https://pubmed.ncbi.nlm.nih.gov/34964438/

3. Kim, Donghwan, Ha, Sang Keun, Gonzalez, Frank J. 2024. CBFA2T3 Is PPARA Sensitive and Attenuates Fasting-Induced Lipid Accumulation in Mouse Liver. In Cells, 13, . doi:10.3390/cells13100831. https://pubmed.ncbi.nlm.nih.gov/38786053/

4. Yan, Tingting, Luo, Yuhong, Yan, Nana, Qu, Aijuan, Gonzalez, Frank J. 2022. Intestinal peroxisome proliferator-activated receptor α-fatty acid-binding protein 1 axis modulates nonalcoholic steatohepatitis. In Hepatology (Baltimore, Md.), 77, 239-255. doi:10.1002/hep.32538. https://pubmed.ncbi.nlm.nih.gov/35460276/