Liver microsomal triglyceride transfer protein is involved in hepatitis C liver steatosis.
OBJECTIVE
Hepatic steatosis is frequent in chronic hepatitis C. Several mechanisms might be implicated, including metabolic cofactors and direct viral effects on intracellular lipid pathways. In a transgenic mouse model, hepatitis C virus (HCV) was shown to inhibit microsomal triglyceride transfer protein (MTP) activity, which is essential for hepatic lipoprotein assembly and secretion. No data are available on liver MTP activity in HCV-infected patients. We therefore investigated liver MTP gene expression and its lipid transfer activity in untreated cases infected with the major HCV genotypes showing variable degrees of hepatic steatosis.


METHODS
MTP messenger RNA (mRNA) levels were measured by real-time polymerase chain reaction, and MTP activity was assessed by fluorescent assay in liver biopsy specimens of 58 HCV-positive patients. A set of metabolic and serum lipid markers was also measured at the time of liver biopsies.


RESULTS
MTP mRNA levels showed a statistically significant (P = .001) inverse correlation with the degree of steatosis, independently of the HCV genotype. MTP mRNA levels also had an inverse correlation with serum insulin (P = .0002), homeostasis model assessment-insulin resistance (HOMA-IR) (P = .005), and body mass index (P = .02) in patients with HCV-1 and HCV-2 and with serum HCV-RNA (P = .02) in HCV-3 patients. Liver MTP-specific activity was significantly reduced in HCV-3 patients compared with those with other HCV genotypes (P = .004) and correlated with reduced serum cholesterol, apo B, and low-density lipoproteins.


CONCLUSIONS
MTP may play a central role in HCV-related steatosis, being modulated by different genotype-specific mechanisms, mainly hyperinsulinemia in non-HCV-3 patients, and more profound and direct virus-related effects in HCV-3-infected individuals.
Mirandola
Silvia
S
VIMM-Venetian Institute of Molecular Medicine, Padova, Italy.
Realdon
Stefano
S
Iqbal
Jahangir
J
Gerotto
Martina
M
Dal Pero
Francesca
F
Bortoletto
Gladis
G
Marcolongo
Moira
M
Vario
Alessandro
A
Datz
Christian
C
Hussain
M Mahmood
MM
Alberti
Alfredo
A
D000328:Adult; D000704:Analysis of Variance; D001483:Base Sequence; D001707:Biopsy, Needle; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D018450:Disease Progression; D005234:Fatty Liver / Q000401:mortality / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation; D005819:Genetic Markers / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000401:mortality / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011336:Probability; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D015996:Survival Rate
D002352:Carrier Proteins; D005819:Genetic Markers; D012333:RNA, Messenger; C106092:microsomal triglyceride transfer protein