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Published on: June 3, 2016
A feed-forward loop amplifies nutritional regulation of PNPLA3
Yongcheng Huang1, Shaoqing He, John Zhong Li
1Departments of Molecular Genetics and Internal Medicine, The Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Summary
Nutrient status regulates patatin-like phospholipase domain-containing protein 3 (PNPLA3) through a feed-forward loop. Carbohydrate feeding increases PNPLA3 transcription via SREBP-1c, while fatty acids enhance PNPLA3 protein stability, impacting nonalcoholic fatty liver disease (NAFLD).
Area of Science:
- Biochemistry
- Molecular Biology
- Hepatology
Background:
- Obesity drives nonalcoholic fatty liver disease (NAFLD) prevalence.
- A PNPLA3 variant (I148M) increases susceptibility to hepatic triglyceride deposition and liver injury.
Purpose of the Study:
- To investigate molecular mechanisms controlling hepatic PNPLA3 expression based on nutrient status.
- To elucidate the role of PNPLA3 in nutrient-induced liver fat accumulation.
Main Methods:
- Quantitative analysis of PNPLA3 mRNA levels under fasting and carbohydrate feeding conditions.
- Chromatin immunoprecipitation and electrophoretic mobility shift assays to map SREBP-1c binding site on the Pnpla3 gene.
- Cultured hepatocyte experiments to assess PNPLA3 protein and mRNA levels following fatty acid and triascin C treatments.
Main Results:
- PNPLA3 mRNA levels surged ~90-fold with carbohydrate feeding, dependent on SREBP-1c.
- SREBP-1c binds to intron 1 of Pnpla3, activating its transcription.
- Fatty acid addition increased PNPLA3 protein mass and prolonged its half-life, independent of triglyceride synthesis.
Conclusions:
- Nutritional control of PNPLA3 involves a feed-forward loop.
- SREBP-1c upregulates PNPLA3 transcription and stimulates fatty acid synthesis, which stabilizes PNPLA3 protein.
- This mechanism contributes to hepatic triglyceride accumulation in NAFLD.
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