Reduction of hepatosteatosis and lipid levels by an adipose differentiation-related protein antisense oligonucleotide.
OBJECTIVE
Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive triglyceride accumulation in hepatocytes. Expression of the lipid droplet protein adipose differentiation-related protein (ADRP) is increased in NAFLD, but whether this is causally linked to hepatic lipid metabolism is unclear. We postulated that a reduction in ADRP would ameliorate hepatic steatosis and improve insulin action.


METHODS
Leptin deficient Lep(ob/ob) and diet-induced obese (DIO) mice were treated with antisense oligonucleotide (ASO) against ADRP, and effects on hepatic and serum lipids and glucose homeostasis were examined.


RESULTS
ADRP ASO specifically decreased ADRP mRNA and protein levels in the livers of Lep(ob/ob) and DIO mice, without altering the levels of other lipid droplet proteins, that is, S3-12 and TIP47. ADRP ASO suppressed expression of lipogenic genes, reduced liver triglyceride content without affecting cholesterol, attenuated triglyceride secretion, and decreased serum triglyceride and alanine aminotransaminase levels. The reduction in hepatic steatosis by ADRP ASO was associated with improvement in glucose homeostasis in both Lep(ob/ob) and DIO mice.


CONCLUSIONS
This study demonstrates a crucial role for the lipid droplet protein ADRP in regulation of lipid metabolism. Reduction in hepatic ADRP level using an antisense oligonucleotide reverses hepatic steatosis, hypertriglyceridemia, and insulin resistance in obese mice, suggesting that ADRP may be targeted for the treatment of NAFLD and associated lipid and glucose abnormalities.
Imai
Yumi
Y
Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19010, USA.
Varela
Gladys M
GM
Jackson
Malaka B
MB
Graham
Mark J
MJ
Crooke
Rosanne M
RM
Ahima
Rexford S
RS
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D005234:Fatty Liver / Q000378:metabolism* / Q000517:prevention & control; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D015228:Hypertriglyceridemia / Q000378:metabolism / Q000517:prevention & control; D007333:Insulin Resistance / Q000502:physiology; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology*; D000070780:Perilipin-2; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D008565:Membrane Proteins; D020320:Oligoribonucleotides, Antisense; D000070780:Perilipin-2; C000602983:Plin2 protein, mouse; D012333:RNA, Messenger; D000410:Alanine Transaminase