Dissociation between fatty liver and insulin resistance in humans carrying a variant of the patatin-like phospholipase 3 gene.
OBJECTIVE
In a genome-wide association scan, the rs738409 C>G single nucleotide polymorphism (SNP) in the patatin-like phospholipase 3 gene (PNPLA3) was strongly associated with increased liver fat but not with insulin resistance estimated from fasting values. We investigated whether the SNP determines liver fat independently of visceral adiposity and whether it may even play a role in protecting from insulin resistance.


METHODS
Liver fat was measured by (1)H magnetic resonance spectroscopy and total and visceral fat by magnetic resonance tomography in 330 subjects. Insulin sensitivity was estimated during an oral glucose tolerance test and the euglycemic-hyperinsulinemic clamp (n = 222). PNPLA3 and tumor necrosis factor-alpha mRNA and triglyceride content were measured in liver biopsies from 16 subjects.


RESULTS
Liver fat correlated strongly with insulin sensitivity (P < 0.0001) independently of age, sex, total fat, and visceral fat. G allele carriers of the SNP rs738409 had higher liver fat (P < 0.0001) and an odds ratio of 2.38 (95% CI 1.37-4.20) for having fatty liver compared to C allele homozygotes. Interestingly, insulin sensitivity (oral glucose tolerance test: P = 0.99; clamp: P = 0.32), serum C-reactive protein levels, lipids, or liver enzymes (all P > 0.14) were not different among the genotypes. Additional adjustment for liver fat actually revealed increased insulin sensitivity in more obese carriers of the G allele (P = 0.01). In liver biopsies triglyceride content correlated positively with expression of the proinflammatory gene tumor necrosis factor-alpha in C allele homozygotes (n = 6, P = 0.027) but not in G allele carriers (n = 10, P = 0.149).


CONCLUSIONS
PNPLA3 may be an important key to understand the mechanisms discriminating fatty liver with and without metabolic consequences.
Kantartzis
Konstantinos
K
Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany.
Peter
Andreas
A
Machicao
Fausto
F
Machann
Jürgen
J
Wagner
Silvia
S
Königsrainer
Ingmar
I
Königsrainer
Alfred
A
Schick
Fritz
F
Fritsche
Andreas
A
Häring
Hans-Ulrich
HU
Stefan
Norbert
N
D000273:Adipose Tissue / Q000033:anatomy & histology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D002097:C-Reactive Protein / Q000378:metabolism; D003596:Cytosine; D005234:Fatty Liver / Q000235:genetics* / Q000473:pathology; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006147:Guanine; D006720:Homozygote; D006801:Humans; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D008049:Lipase / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
D002097:C-Reactive Protein; D003596:Cytosine; D006147:Guanine; D007328:Insulin; D008049:Lipase; D008055:Lipids; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent