Role of dipeptidyl peptidase IV (DPP4) in the development of dyslipidemia: DPP4 contributes to the steroid metabolism pathway.
OBJECTIVE
We previously reported that dipeptidyl peptidase IV (DPP4)-deficient rats were susceptible to dyslipidemia induced by streptozotocin (STZ). Hence, it is suggested that DPP4 is important for lipid metabolism.


METHODS
In this study, to verify the role of DPP4 in the development of dyslipidemia, we carried out a microarray analysis of the livers of STZ-treated wild-type and DPP4-deficient rats and showed that the expression levels of genes involved in metabolic processes (steroid metabolic processes and cellular lipid metabolic processes) were significantly altered by STZ treatment.


RESULTS
In the wild-type rats, the expression of hydroxysteroid (17-beta) dehydrogenase 2 (Hsd7b2), which catalyzes sex steroid synthesis from cholesterol, was significantly increased by about 15-fold after STZ treatment; however, it did not change in the DPP4-deficient rats. In the STZ untreated group of DPP4-deficient rats, the expression levels of cytochrome P450, subfamily 51 (Cyp51) and sterol-C4-methyl oxidase-like (Sc4mol), which catalyze intermediate steps in cholesterol synthesis, were significantly elevated compared to those of other groups. Similar results were demonstrated in HuH7-cells after DPP4 overexpression or the addition of human sera containing DPP4.


CONCLUSIONS
DPP4 is crucial for regulating the expression of factors related to steroid metabolism such as Cyp51, Sc4mol, and Hsd17b2, and DPP4 deficiency or inhibition may cause dyslipidemia.
Department of Pharmaceutical Information Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan. sato@ph.tokushima-u.ac.jp
Youichi
Y
Sato
Sakura
S
Koshioka
Yasushi
Y
Kirino
Takayuki
T
Kamimoto
Kazuyoshi
K
Kawazoe
Shinji
S
Abe
Kazuo
K
Minakuchi
Yutaka
Y
Nakahori
D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D050171:Dyslipidemias / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D004960:Estradiol Dehydrogenases / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058886:Sterol 14-Demethylase / Q000378:metabolism; D013311:Streptozocin / Q000494:pharmacology
D013311:Streptozocin; D002784:Cholesterol; D015067:17-Hydroxysteroid Dehydrogenases; C578614:Hsd17b2 protein, rat; D004960:Estradiol Dehydrogenases; D058886:Sterol 14-Demethylase; D018819:Dipeptidyl Peptidase 4