Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease. To elucidate the molecular basis of NAFLD, we performed an exome-wide association study of liver fat content. Three variants were associated with higher liver fat levels at the exome-wide significance level of 3.6 × 10(-7): two in PNPLA3, an established locus for NAFLD, and one (encoding p.Glu167Lys) in TM6SF2, a gene of unknown function. The TM6SF2 variant encoding p.Glu167Lys was also associated with higher circulating levels of alanine transaminase, a marker of liver injury, and with lower levels of low-density lipoprotein-cholesterol (LDL-C), triglycerides and alkaline phosphatase in 3 independent populations (n > 80,000). When recombinant protein was expressed in cultured hepatocytes, 50% less Glu167Lys TM6SF2 protein was produced relative to wild-type TM6SF2. Adeno-associated virus-mediated short hairpin RNA knockdown of Tm6sf2 in mice increased liver triglyceride content by threefold and decreased very-low-density lipoprotein (VLDL) secretion by 50%. Taken together, these data indicate that TM6SF2 activity is required for normal VLDL secretion and that impaired TM6SF2 function causally contributes to NAFLD.
| Original language | English |
|---|---|
| Journal | Nature Genetics |
| Volume | 46 |
| Issue number | 4 |
| Pages (from-to) | 352-356 |
| Number of pages | 5 |
| ISSN | 1061-4036 |
| DOIs | |
| Publication status | Published - Apr 2014 |
Keywords
- Adipose Tissue
- Alanine Transaminase
- Amino Acid Sequence
- Animals
- Base Sequence
- Chromatography, Liquid
- Dependovirus
- Exome
- Fatty Liver
- Gene Knockdown Techniques
- Genetic Association Studies
- Genetic Predisposition to Disease
- Hepatocytes
- Humans
- Lipoproteins, VLDL
- Liver
- Membrane Proteins
- Mice
- Molecular Sequence Data
- Mutation, Missense
- Non-alcoholic Fatty Liver Disease
- Real-Time Polymerase Chain Reaction
- Recombinant Proteins
- Sequence Alignment
- Sequence Analysis, DNA
- Triglycerides