Activation of the farnesoid X receptor improves lipid metabolism in combined hyperlipidemic hamsters.
The transcription factor farnesoid X receptor (FXR) has recently been implicated in the control of hepatic triglyceride production. Activation of FXR may ameliorate hypertriglyceridemia, a cardinal feature of the metabolic syndrome. Because hamsters share many characteristic features of human lipid metabolism, we used a high-fructose-fed hamster model to study the impact of FXR activation with chenodeoxycholic acid (CDCA) on plasma lipoprotein metabolism. Male Syrian hamsters fed a diet containing 60% kcal from fructose for 2 wk developed hypertriglyceridemia and hypercholesterolemia (+120 and +60%, P = 0.005 and 0.0004 vs. controls) due to increased hepatic lipoprotein production. This could be largely attributed to enhanced hepatic de novo lipogenesis, as indicated by increased expression of sterol regulatory element-binding protein-1, fatty acid synthase, and steaoryl-CoA desaturase-1. Lipoprotein analysis demonstrated that the increase in plasma triglycerides occurred in the VLDL density range, whereas increases in VLDL, IDL/LDL, and HDL cholesterol accounted for the elevated plasma cholesterol concentrations. Addition of 0.1% CDCA to the high-fructose diet decreased hepatic de novo lipogenesis and consequently triglyceride production and prevented the increases in plasma triglycerides and cholesterol (-40 and -18%, P = 0.03 and 0.03 vs. high fructose-fed animals). CDCA-treated animals had lower VLDL triglycerides and decreased VLDL and IDL/LDL cholesterol plasma concentrations. These data demonstrate that activation of FXR with CDCA effectively lowers plasma triglyceride and cholesterol concentrations, mainly by decreasing de novo lipogenesis and hepatic secretion of triglyceride-rich lipoproteins. Our studies identify activators of FXR as promising new tools in the therapy of hypertriglyceridemic states, including the insulin resistance syndrome and type 2 diabetes.
Bilz
Stefan
S
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06536-8012, USA.
Samuel
Varman
V
Morino
Katsutaro
K
Savage
David
D
Choi
Cheol Soo
CS
Shulman
Gerald I
GI
D000818:Animals; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000378:metabolism*; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D006949:Hyperlipidemias / Q000097:blood / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology*; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013230:Stearoyl-CoA Desaturase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D002635:Chenodeoxycholic Acid; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D004268:DNA-Binding Proteins; D064429:Fatty Acid Synthases; D008074:Lipoproteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013230:Stearoyl-CoA Desaturase; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated