Nobiletin Prevents High-Fat Diet-Induced Dysregulation of Intestinal Lipid Metabolism and Attenuates Postprandial Lipemia.

Autor:	Morrow NM; Molecular Medicine, Robarts Research Institute (N.M.M., D.E.T., S.S.C., B.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada.; Department of Biochemistry (N.M.M., S.S.C., M.W.H.), The University of Western Ontario, London, Canada.; The University of Ottawa Heart Institute, Ontario, Canada (N.M.M., N.A.T., A.A.H., E.F., E.E.M.).; Department of Biochemistry, Microbiology and Immunology, The University of Ottawa, Faculty of Medicine, ON (N.M.M., N.A.T., A.A.H., E.F., E.E.M.)., Trzaskalski NA; The University of Ottawa Heart Institute, Ontario, Canada (N.M.M., N.A.T., A.A.H., E.F., E.E.M.).; Department of Biochemistry, Microbiology and Immunology, The University of Ottawa, Faculty of Medicine, ON (N.M.M., N.A.T., A.A.H., E.F., E.E.M.)., Hanson AA; The University of Ottawa Heart Institute, Ontario, Canada (N.M.M., N.A.T., A.A.H., E.F., E.E.M.).; Department of Biochemistry, Microbiology and Immunology, The University of Ottawa, Faculty of Medicine, ON (N.M.M., N.A.T., A.A.H., E.F., E.E.M.)., Fadzeyeva E; The University of Ottawa Heart Institute, Ontario, Canada (N.M.M., N.A.T., A.A.H., E.F., E.E.M.).; Department of Biochemistry, Microbiology and Immunology, The University of Ottawa, Faculty of Medicine, ON (N.M.M., N.A.T., A.A.H., E.F., E.E.M.)., Telford DE; Molecular Medicine, Robarts Research Institute (N.M.M., D.E.T., S.S.C., B.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada.; Department of Medicine (D.E.T., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada., Chhoker SS; Molecular Medicine, Robarts Research Institute (N.M.M., D.E.T., S.S.C., B.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada.; Department of Biochemistry (N.M.M., S.S.C., M.W.H.), The University of Western Ontario, London, Canada., Sutherland BG; Molecular Medicine, Robarts Research Institute (N.M.M., D.E.T., S.S.C., B.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada., Edwards JY; Molecular Medicine, Robarts Research Institute (N.M.M., D.E.T., S.S.C., B.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada.; Department of Medicine (D.E.T., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada., Huff MW; Molecular Medicine, Robarts Research Institute (N.M.M., D.E.T., S.S.C., B.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada.; Department of Biochemistry (N.M.M., S.S.C., M.W.H.), The University of Western Ontario, London, Canada.; Department of Medicine (D.E.T., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada., Mulvihill EE; The University of Ottawa Heart Institute, Ontario, Canada (N.M.M., N.A.T., A.A.H., E.F., E.E.M.).; Centre for Infection, Immunity and Inflammation, Ottawa, Ontario, Canada (E.E.M).; Montreal Diabetes Research Group, Montreal, Quebec, Canada (E.E.M).; Department of Biochemistry, Microbiology and Immunology, The University of Ottawa, Faculty of Medicine, ON (N.M.M., N.A.T., A.A.H., E.F., E.E.M.).
Jazyk:	angličtina
Zdroj:	Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2022 Feb; Vol. 42 (2), pp. 127-144. Date of Electronic Publication: 2021 Dec 16.
DOI:	10.1161/ATVBAHA.121.316896
Abstrakt:	Objective: Nobiletin is a dietary flavonoid that improves insulin resistance and atherosclerosis in mice with metabolic dysfunction. Dysregulation of intestinal lipoprotein metabolism contributes to atherogenesis. The objective of the study was to determine if nobiletin targets the intestine to improve metabolic dysregulation in both male and female mice. Approach and Results: Triglyceride-rich lipoprotein (TRL) secretion, intracellular triglyceride kinetics, and intestinal morphology were determined in male and female LDL (low-density lipoprotein) receptor knockout ( Ldlr -/- ), and male wild-type mice fed a standard laboratory diet or high-fat, high-cholesterol (HFHC) diet ± nobiletin using an olive oil gavage, radiotracers, and electron microscopy. Nobiletin attenuated postprandial TRL levels in plasma and enhanced TRL clearance. Nobiletin reduced fasting jejunal triglyceride accumulation through accelerated TRL secretion and lower jejunal fatty acid synthesis with no impact on fatty acid oxidation. Fasting-refeeding experiments revealed that nobiletin led to higher levels of phosphorylated AKT (protein kinase B) and FoxO1 (forkhead box O1) and normal Srebf1c expression indicating increased insulin sensitivity. Intestinal length and weight were diminished by HFHC feeding and restored by nobiletin. Both fasting and postprandial plasma GLP-1 (glucagon-like peptide-1; and likely GLP-2) were elevated in response to nobiletin. Treatment with a GLP-2 receptor antagonist, GLP-2(3-33), reduced villus length in HFHC-fed mice but did not impact TRL secretion in any diet group. In contrast to males, nobiletin did not improve postprandial lipid parameters in female mice. Conclusions: Nobiletin opposed the effects of the HFHC diet by normalizing intestinal de novo lipogenesis through improved insulin sensitivity. Nobiletin prevents postprandial lipemia because the enhanced TRL clearance more than compensates for increased TRL secretion.
Databáze:	MEDLINE
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