rs1800591 — MTTP MTTP -493G/T

MTTP -493G/T — The Promoter Variant That Quiets Hepatic Fat Export

Your liver continuously performs a balancing act: synthesize and receive fats, then package and ship them out as VLDL particles¹¹ VLDL particles
Very-low-density lipoprotein: triglyceride-rich particles assembled in the liver and secreted into the bloodstream, where they deliver fat to peripheral tissues. The enzyme that loads triglycerides into those outbound VLDL packages is MTTP — microsomal triglyceride transfer protein²² MTTP — microsomal triglyceride transfer protein
MTTP transfers triglycerides, phospholipids, and cholesteryl esters onto nascent apolipoprotein B during VLDL assembly. Without functional MTTP, triglycerides cannot be exported and instead accumulate within hepatocytes. A common polymorphism in the MTTP promoter region — rs1800591, known in the literature as the -493G/T variant — directly controls how much MTTP the liver makes, and therefore how efficiently it clears fat.

The Mechanism

The -493G/T variant sits in the promoter region upstream of the MTTP gene. A 2008 functional study³³ 2008 functional study
Rubin et al., Human Mutation, 2008, PMID 17854051 dissected promoter activity across MTTP haplotypes in hepatic cells, finding that the common haplotype carrying the -493G allele showed approximately two-fold lower transcriptional activity⁴⁴ two-fold lower transcriptional activity
Rubin et al. demonstrated that differences at nearby positions — particularly -164 — govern SREBP1a binding affinity, and -493G travels in linkage with the lower-activity haplotype across most European populations than the rarer haplotype carrying the -493T allele. The mechanism operates through differential binding of SREBP1a⁵⁵ SREBP1a
Sterol regulatory element binding protein 1a: a transcription factor that activates genes involved in lipid synthesis and transport — the T allele promotes a promoter configuration that recruits SREBP1a more effectively, driving higher MTTP expression. The downstream consequence of the G allele's reduced expression: less MTTP protein, less efficient triglyceride loading onto VLDL, and greater hepatic triglyceride retention.

The Evidence

The earliest clinical evidence came from a 2004 Japanese study⁶⁶ 2004 Japanese study
Namikawa et al., Journal of Hepatology, 2004, 63 biopsy-confirmed NASH patients vs 150 controls. The G allele was significantly more frequent in NASH cases (P=0.001), and homozygous G/G patients showed more advanced NASH histology than G/T carriers (P=0.04) — a dose-response pattern consistent with the variant acting through reduced MTTP expression rather than chance association.

Two independent meta-analyses in 2014 reinforced this finding. Zheng et al.⁷⁷ Zheng et al.
11 case-control studies, 636 NAFLD cases and 918 controls, DNA and Cell Biology, 2014 found the MTP -493G/T polymorphism was "strongly correlated with an increased risk of NAFLD" across both Caucasian and non-Caucasian populations. Li et al.⁸⁸ Li et al.
11 studies in a complementary analysis, Genetics and Molecular Research, 2014 quantified the risk: G allele vs T allele OR = 1.39 (95% CI 1.17–1.65, P<0.001); dominant model (GG+GT vs TT) OR = 1.46 (95% CI 1.02–2.09).

A larger 2020 meta-analysis⁹⁹ larger 2020 meta-analysis
Tan et al., Saudi Journal of Gastroenterology, 10 studies, 1,388 NAFLD cases and 1,690 controls found no significant overall correlation between rs1800591 and general NAFLD (OR 1.08, P=0.76), but when the analysis was restricted to biopsy-confirmed NASH patients, the G allele emerged strongly: heterozygote model GT vs TT OR = 3.16 (95% CI 1.13–8.83) and dominant model GT+GG vs TT OR = 3.03 (95% CI 1.13–8.09). This pattern — stronger association with NASH than with simple steatosis — is consistent with the variant's effect on MTTP expression amplifying the progression to hepatic inflammation rather than merely increasing fat deposition.

In the context of chronic hepatitis C¹⁰¹⁰ chronic hepatitis C
Prata et al. 2022, 236 HCV-infected patients, Clinics (Sao Paulo), the interaction is dramatically amplified: GT/TT genotype combined with HCV genotype 3 produced an 11.51-fold increase in steatosis risk (OR 11.51, 95% CI 2.08–63.59), a gene-virus interaction that dwarfs the variant's independent effect. HCV genotype 3 is itself steatogenic, and reduced MTTP-mediated fat export appears to compound the viral lipid dysregulation.

Practical Actions

The G allele is the common form — roughly 56% of people are G/G homozygotes. What the evidence shows is that this common background state is associated with a modestly less efficient hepatic fat export system. The T allele (approximately 25% frequency globally) is the rarer, higher-expression variant that confers somewhat better MTTP-mediated VLDL secretion and a lower risk of hepatic triglyceride accumulation.

For G/G homozygotes, the key clinical implication is that dietary and metabolic factors imposing hepatic triglyceride load — saturated fat, fructose, alcohol — meet a slightly less efficient clearance system. Diets high in these substrates may promote hepatic fat retention more readily than in T/T individuals. Reducing hepatic triglyceride substrate (through limiting saturated fat and refined carbohydrates) and avoiding alcohol directly addresses the bottleneck this variant creates.

T/T homozygotes carry two copies of the higher-expression promoter variant and appear to have the most efficient MTTP-driven hepatic fat export, conferring measurably lower hepatic triglyceride accumulation and NASH risk. This is a relatively rare genotype (~6% globally).

Interactions

The most clinically important interaction is with HCV genotype 3 infection: reduced MTTP expression (G allele) combined with HCV genotype 3's intrinsic steatogenicity creates a 11.5-fold elevation in steatosis risk. Any G-allele carrier with known or suspected hepatitis C infection should have this discussed with their hepatologist.

Within the MTTP gene itself, rs1800591 interacts biologically with the coding variant rs3816873 (MTTP I128T): rs1800591 controls how much MTTP protein is made, while rs3816873 affects the functional properties of the protein made. Carriers of the G allele at rs1800591 who also carry the T/T (Ile128) genotype at rs3816873 may face a double disadvantage — both reduced MTTP expression and a less efficient form of the protein produced. The reverse combination (T allele at rs1800591 + C allele at rs3816873) would represent the highest-expression and most-efficient MTTP phenotype.

MTTP also functions downstream of PNPLA3 rs738409 (I148M): PNPLA3 governs triglyceride hydrolysis inside hepatocytes, generating substrates for MTTP to load onto VLDL. G/G carriers at rs1800591 who also carry PNPLA3 GG (I148M homozygous — impaired hydrolysis) face both impaired substrate mobilization (PNPLA3) and impaired export (MTTP), a convergent hepatic triglyceride retention risk that exceeds either variant alone.