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Genetic variation in PNPLA3 (adiponutrin) confers sensitivity to weight loss-induced decrease in liver fat in humans
Ksenia Sevastianova1, Anna Kotronen, Amalia Gastaldelli
1Minerva Foundation Institute for Medical Research, Helsinki, Finland. ksenia.sevastianova@helsinki.fi
The American Journal of Clinical Nutrition
|April 29, 2011
Summary
Weight loss effectively reduces liver fat in individuals with the PNPLA3 I148M mutation, regardless of their rs738409 genotype. This finding highlights the therapeutic potential of weight reduction for managing liver fat accumulation.
Area of Science:
- Genetics
- Metabolic Diseases
- Hepatology
Background:
- The rs738409 C→G polymorphism in patatin-like phospholipase domain-containing 3 (PNPLA3) results in an I148M missense mutation.
- This PNPLA3 I148M mutation is linked to elevated liver fat but not insulin resistance.
- Carriers of the mutation face an increased risk of severe liver disease due to impaired triglyceride hydrolysis.
Purpose of the Study:
- To investigate if the rs738409 PNPLA3 G allele affects the efficacy of weight loss in reducing liver fat.
- To determine the influence of the PNPLA3 G allele on changes in insulin sensitivity following weight loss.
Main Methods:
- Recruited subjects homozygous for the PNPLA3 G allele (PNPLA3-148MM) and C allele (PNPLA3-148II).
- Matched groups for baseline age, sex, BMI, and liver fat; subjects underwent a 6-day hypocaloric, low-carbohydrate diet.
- Measured liver fat (proton magnetic resonance spectroscopy), whole-body insulin sensitivity (euglycemic clamp), and lipolysis ([(2)H(5)]glycerol infusion) pre- and post-diet.
Main Results:
- Weight loss was comparable between the PNPLA3-148MM (-3.1 kg) and PNPLA3-148II (-3.1 kg) groups.
- Liver fat significantly decreased by 45% in the PNPLA3-148MM group (P < 0.001) and 18% in the PNPLA3-148II group (P < 0.01).
- Baseline fasting insulin and C-peptide were lower in the PNPLA3-148MM group.
Conclusions:
- Weight loss is a potent intervention for reducing liver fat in individuals with both rs738409 PNPLA3 G and C alleles.
- The study demonstrates that weight loss can effectively decrease liver fat irrespective of the rs738409 genotype.
- Trial registered at www.hus.fi as 233775.
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