Docosahexaenoic acid inhibits proteolytic processing of sterol regulatory element-binding protein-1c (SREBP-1c) via activation of AMP-activated kinase.
In hyperinsulinemic states including obesity and T2DM, overproduction of fatty acid and triglyceride contributes to steatosis of the liver, hyperlipidemia and hepatic insulin resistance. This effect is mediated in part by the transcriptional regulator sterol responsive element binding protein-1c (SREBP-1c), which stimulates the expression of genes involved in hepatic fatty acid and triglyceride synthesis. SREBP-1c is up regulated by insulin both via increased transcription of nascent full-length SREBP-1c and by enhanced proteolytic processing of the endoplasmic reticulum (ER)-bound precursor to yield the transcriptionally active n-terminal form, nSREBP-1c. Polyunsaturated fatty acids of marine origin (n-3 PUFA) prevent induction of SREBP-1c by insulin thereby reducing plasma and hepatic triglycerides. Despite widespread use of n-3 PUFA supplements to reduce triglycerides in clinical practice, the exact mechanisms underlying their hypotriglyceridemic effect remain elusive. Here we demonstrate that the n-3 PUFA docosahexaenoic acid (DHA; 22:5 n-3) reduces nSREBP-1c by inhibiting regulated intramembrane proteolysis (RIP) of the nascent SREBP-1c. We further show that this effect of DHA is mediated both via activation of AMP-activated protein kinase (AMPK) and by inhibition of mechanistic target of rapamycin complex 1 (mTORC1). The inhibitory effect of AMPK on SREBP-1c processing is linked to phosphorylation of serine 365 of SREBP-1c in the rat. We have defined a novel regulatory mechanism by which n-3 PUFA inhibit induction of SREBP-1c by insulin. These findings identify AMPK as an important negative regulator of hepatic lipid synthesis and as a potential therapeutic target for hyperlipidemia in obesity and T2DM.
Department of Veterans Affairs Medical Center, 1030 Jefferson Avenue, Memphis TN 38104, United States; Department of Pharmacology, 874 Union Avenue, Memphis, TN 38163, United States. Electronic address: xdeng@uthsc.edu.
Xiong
X
Deng
Department of Pharmacology, 874 Union Avenue, Memphis, TN 38163, United States.
Qingming
Q
Dong
Department of Physiology, 894 Union Avenue, Memphis TN 38163, United States; Children's Foundation Research Institute, Le Bonheur Children's Hospital, Department of Pediatrics, University of Tennessee Health Science Center, 50 North Dunlap, Memphis TN 38103, United States.
Dave
D
Bridges
Department of Veterans Affairs Medical Center, 1030 Jefferson Avenue, Memphis TN 38104, United States; Department of Pharmacology, 874 Union Avenue, Memphis, TN 38163, United States.
Rajendra
R
Raghow
Department of Veterans Affairs Medical Center, 1030 Jefferson Avenue, Memphis TN 38104, United States; Department of Pharmacology, 874 Union Avenue, Memphis, TN 38163, United States.
Edwards A
EA
Park
Department of Veterans Affairs Medical Center, 1030 Jefferson Avenue, Memphis TN 38104, United States; Department of Pharmacology, 874 Union Avenue, Memphis, TN 38163, United States.
Marshall B
MB
Elam
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D006949:Hyperlipidemias / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000178:diet therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D059748:Proteolysis / Q000187:drug effects*; D051381:Rats; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
D007328:Insulin; D046912:Multiprotein Complexes; D051780:Sterol Regulatory Element Binding Protein 1; D004281:Docosahexaenoic Acids; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
AMP kinase; Docosahexanaenoic acid; Insulin; Lipogenesis; SREBP-1c