Measurement of fat/water ratios in rat liver using 3D three-point dixon MRI.
Hepatic steatosis, or fatty liver, is commonly observed during the animal phase of drug safety studies. A noninvasive three-dimensional (3D) three-point Dixon method was used to quantitatively evaluate the fatty livers of rats induced by an experimental microsomal transfer protein (MTP) inhibitor, in an effort to develop a safety biomarker that could be translated to human studies. The method was implemented at 2.0 T for in vivo studies, and at 7.1 T for higher-resolution magnetic resonance (MR) histologic studies. In three separate protocols to study dose response and longitudinal evolution, intrahepatic fatty accumulation was detected by this method and confirmed by chemical and histologic assessments. Consistent with the pathologic changes, the fat/water ratios estimated by the MR technique increased significantly at doses of 1 mg/kg and 100 mg/kg of MTP inhibitor after 14 days of continuous administration. Among the more important findings were: 1). with the 3D three-point Dixon method, in vivo longitudinal studies of liver fat distribution can be conducted at significantly higher resolution than has previously been reported; 2). MR histology allows delineation of distribution at the microscopic scale of 0.0024 mm(3) resolution; and 3). the 3D three-point Dixon technique provides relative estimates of liver fat content and distribution at a high confidence level. This technique will be applicable in future studies in which fatty liver is a potential safety issue.
Zhang
Xiaowei
X
Center for In Vivo Microscopy, Duke University Medical Center, Durham, North Carolina 27710, USA.
Tengowski
Mark
M
Fasulo
Lisa
L
Botts
Suzanne
S
Suddarth
Steve A
SA
Johnson
G Allan
GA
D000273:Adipose Tissue / Q000473:pathology*; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001834:Body Water / Q000737:chemistry*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005234:Fatty Liver / Q000139:chemically induced / Q000175:diagnosis* / Q000473:pathology; D005260:Female; D006801:Humans; D007089:Image Enhancement / Q000379:methods; D021621:Imaging, Three-Dimensional / Q000379:methods*; D008099:Liver / Q000473:pathology*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008862:Microsomes, Liver / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D015415:Biomarkers; D002352:Carrier Proteins; C106092:microsomal triglyceride transfer protein