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- Gustafsson, Maria, 1976, et al.
(författare)
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Retention of Low-Density Lipoprotein in Atherosclerotic Lesions of the Mouse. Evidence for a Role of Lipoprotein Lipase
- 2007
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Ingår i: Circ Res. - 1524-4571. ; 101:8, s. 777-783
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Tidskriftsartikel (refereegranskat)abstract
- Direct binding of apolipoprotein (apo)B-containing lipoproteins to proteoglycans is the initiating event in atherosclerosis, but the processes involved at later stages of development are unclear. Here, we investigated the importance of the apoB-proteoglycan interaction in the development of atherosclerosis over time and investigated the role of lipoprotein lipase (LPL) to facilitate low-density lipoprotein (LDL) retention at later stages of development. Atherosclerosis was analyzed in apoB transgenic mice expressing LDL with normal (control LDL) or reduced proteoglycan-binding (RK3359-3369SA LDL) activity after an atherogenic diet for 0 to 40 weeks. The initiation of atherosclerosis was delayed in mice expressing RK3359-3369SA LDL, but they eventually developed the same level of atherosclerosis as mice expressing control LDL. Retention studies in vivo showed that although higher levels of (131)I-tyramine cellobiose-labeled control LDL ((131)I-TC-LDL) were retained in nonatherosclerotic aortae compared with RK3359-3369SA (131)I-TC-LDL, the retention was significantly higher and there was no difference between the groups in atherosclerotic aortae. Lower levels of control (125)I-TC-LDL and RK3359-3369SA (125)I-TC-LDL were retained in atherosclerotic aortae from ldlr(-/-) mice transplanted with lpl(-/-) compared with lpl(+/+) bone marrow. Uptake of control LDL or RK3359-3369SA LDL into macrophages with specific expression of human catalytically active or inactive LPL was increased compared with control macrophages. Furthermore, transgenic mice expressing catalytically active or inactive LPL developed the same extent of atherosclerosis. Thus, retention of LDL in the artery wall is initiated by direct LDL-proteoglycan binding but shifts to indirect binding with bridging molecules such as LPL.
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- Bäckhed, Fredrik, 1973, et al.
(författare)
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Mechanisms underlying the resistance to diet-induced obesity in germ-free mice
- 2007
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Ingår i: Proc Natl Acad Sci U S A. ; 104:3, s. 979-984
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Tidskriftsartikel (refereegranskat)abstract
- The trillions of microbes that colonize our adult intestines function collectively as a metabolic organ that communicates with, and complements, our own human metabolic apparatus. Given the worldwide epidemic in obesity, there is interest in how interactions between human and microbial metabolomes may affect our energy balance. Here we report that, in contrast to mice with a gut microbiota, germ-free (GF) animals are protected against the obesity that develops after consuming a Western-style, high-fat, sugar-rich diet. Their persistently lean phenotype is associated with increased skeletal muscle and liver levels of phosphorylated AMP-activated protein kinase (AMPK) and its downstream targets involved in fatty acid oxidation (acetylCoA carboxylase; carnitine-palmitoyltransferase). Moreover, GF knockout mice lacking fasting-induced adipose factor (Fiaf), a circulating lipoprotein lipase inhibitor whose expression is normally selectively suppressed in the gut epithelium by the microbiota, are not protected from diet-induced obesity. Although GF Fiaf-/- animals exhibit similar levels of phosphorylated AMPK as their wild-type littermates in liver and gastrocnemius muscle, they have reduced expression of genes encoding the peroxisomal proliferator-activated receptor coactivator (Pgc-1alpha) and enzymes involved in fatty acid oxidation. Thus, GF animals are protected from diet-induced obesity by two complementary but independent mechanisms that result in increased fatty acid metabolism: (i) elevated levels of Fiaf, which induces Pgc-1alpha; and (ii) increased AMPK activity. Together, these findings support the notion that the gut microbiota can influence both sides of the energy balance equation, and underscore the importance of considering our metabolome in a supraorganismal context.
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- Bäckhed, Fredrik, 1973, et al.
(författare)
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The gut microbiota as an environmental factor that regulates fat storage
- 2004
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Ingår i: Proc Natl Acad Sci U S A. - : Proceedings of the National Academy of Sciences. ; 101:44, s. 15718-15723
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Tidskriftsartikel (refereegranskat)abstract
- New therapeutic targets for noncognitive reductions in energy intake, absorption, or storage are crucial given the worldwide epidemic of obesity. The gut microbial community (microbiota) is essential for processing dietary polysaccharides. We found that conventionalization of adult germ-free (GF) C57BL/6 mice with a normal microbiota harvested from the distal intestine (cecum) of conventionally raised animals produces a 60% increase in body fat content and insulin resistance within 14 days despite reduced food intake. Studies of GF and conventionalized mice revealed that the microbiota promotes absorption of monosaccharides from the gut lumen, with resulting induction of de novo hepatic lipogenesis. Fasting-induced adipocyte factor (Fiaf), a member of the angiopoietin-like family of proteins, is selectively suppressed in the intestinal epithelium of normal mice by conventionalization. Analysis of GF and conventionalized, normal and Fiaf knockout mice established that Fiaf is a circulating lipoprotein lipase inhibitor and that its suppression is essential for the microbiota-induced deposition of triglycerides in adipocytes. Studies of Rag1-/- animals indicate that these host responses do not require mature lymphocytes. Our findings suggest that the gut microbiota is an important environmental factor that affects energy harvest from the diet and energy storage in the host.
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