Plasma lipid profiling across species for the identification of optimal animal models of human dyslipidemia.
In an attempt to understand the applicability of various animal models to dyslipidemia in humans and to identify improved preclinical models for target discovery and validation for dyslipidemia, we measured comprehensive plasma lipid profiles in 24 models. These included five mouse strains, six other nonprimate species, and four nonhuman primate (NHP) species, and both healthy animals and animals with metabolic disorders. Dyslipidemic humans were assessed by the same measures. Plasma lipoprotein profiles, eight major plasma lipid fractions, and FA compositions within these lipid fractions were compared both qualitatively and quantitatively across the species. Given the importance of statins in decreasing plasma low-density lipoprotein cholesterol for treatment of dyslipidemia in humans, the responses of these measures to simvastatin treatment were also assessed for each species and compared with dyslipidemic humans. NHPs, followed by dog, were the models that demonstrated closest overall match to dyslipidemic humans. For the subset of the dyslipidemic population with high plasma triglyceride levels, the data also pointed to hamster and db/db mouse as representative models for practical use in target validation. Most traditional models, including rabbit, Zucker diabetic fatty rat, and the majority of mouse models, did not demonstrate overall similarity to dyslipidemic humans in this study.
Department of Atherosclerosis, Merck Research Laboratories, Rahway, NJ 07065, USA.
Wu
W
Yin
Ester
E
Carballo-Jane
David G
DG
McLaren
Vivienne H
VH
Mendoza
Karen
K
Gagen
Neil S
NS
Geoghagen
Lesley Ann
LA
McNamara
Judith N
JN
Gorski
George J
GJ
Eiermann
Aleksandr
A
Petrov
Michael
M
Wolff
Xinchun
X
Tong
Larissa C
LC
Wilsie
Taro E
TE
Akiyama
Jing
J
Chen
Anil
A
Thankappan
Jiyan
J
Xue
Xiaoli
X
Ping
Genevieve
G
Andrews
L Alexandra
LA
Wickham
Cesaire L
CL
Gai
Tu
T
Trinh
Alison A
AA
Kulick
Marcie J
MJ
Donnelly
Gregory O
GO
Voronin
Ray
R
Rosa
Anne-Marie
AM
Cumiskey
Kavitha
K
Bekkari
Lyndon J
LJ
Mitnaul
Oscar
O
Puig
Fabian
F
Chen
Richard
R
Raubertas
Peggy H
PH
Wong
Barbara C
BC
Hansen
Ken S
KS
Koblan
Thomas P
TP
Roddy
Brian K
BK
Hubbard
Alison M
AM
Strack
D000818:Animals; D006224:Cricetinae; D004195:Disease Models, Animal; D004285:Dogs; D050171:Dyslipidemias / Q000097:blood* / Q000188:drug therapy; D005227:Fatty Acids / Q000097:blood; D006801:Humans; D008055:Lipids / Q000097:blood*; D051379:Mice; D011323:Primates; D019821:Simvastatin / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood
D005227:Fatty Acids; D008055:Lipids; D014280:Triglycerides; D019821:Simvastatin