Apolipoprotein A-V deficiency enhances chylomicron production in lymph fistula mice

Abstract

Apolipoprotein A-V (apoA-V), a liver-synthesized apolipoprotein discovered in 2001, strongly modulates fasting plasma triglycerides (TG). Little is reported on the effect of apoA-V on postprandial plasma TG, an independent predictor for atherosclerosis. Overexpressing apoA-V in mice suppresses postprandial TG, but mechanisms focus on increased lipolysis or clearance of remnant particles. Unknown is whether apoA-V suppresses the absorption of dietary lipids by the gut. This study examines how apoA-V deficiency affects the steady-state absorption and lymphatic transport of dietary lipids in chow-fed mice. Using apoA-V knockout (KO, n ϭ 8) and wild-type (WT, n ϭ 8) lymph fistula mice, we analyzed the uptake and lymphatic transport of lipids during a continuous infusion of an emulsion containing [ 3 H]triolein and [14 C]cholesterol. ApoA-V KO mice showed a twofold increase in 3 H (P Ͻ 0.001) and a threefold increase in 14 C (P Ͻ 0.001) transport into the lymph compared with WT. The increased lymphatic transport was accompanied by a twofold reduction (P Ͻ 0.05) in mucosal 3 H, suggesting that apoA-V KO mice more rapidly secreted [3 H]TG out of the mucosa into the lymph. ApoA-V KO mice also produced chylomicrons more rapidly than WT (P Ͻ 0.05), as measured by the transit time of [ 14 C]oleic acid from the intestinal lumen to lymph. Interestingly, apoA-V KO mice produced a steadily increasing number of chylomicron particles over time, as measured by lymphatic apoB output. The data suggest that apoA-V suppresses the production of chylomicrons, playing a previously unknown role in lipid metabolism that may contribute to the postprandial hypertriglyceridemia associated with apoA-V deficiency. absorption; intestine AFTER DIETARY FAT INTAKE, the increase of plasma triglycerides (TG) is a normal metabolic consequence characterized by a transient accumulation of TG-rich lipoproteins comprised of intestinally derived chylomicrons and liver-derived very low density lipoprotein (VLDL). Hydrolysis of their TG cores releases free fatty acids to be taken up by muscle and adipose tissues, generating remnant particles that are efficiently removed from the circulation by the liver. Aberrations in lipoprotein metabolism result in elevated plasma TG and a prolonged accumulation of remnant particles that are atherogenic (16,76,24) and constitute a major risk factor for cardiovascular disease (51,43).Apolipoproteins play crucial roles in the regulation of lipoprotein metabolism by acting as structural proteins, as cofactors for enzymes involved in lipolysis, or as ligands for receptor-mediated clearance of lipoproteins (35). Apolipoprotein A-V (apoA-V) was discovered in 2001 to be expressed exclusively in the liver and located ϳ30 kb proximal to the APOAI/ CIII/AIV gene cluster (49, 69), a region well-known for regulating lipid metabolism (19). Early studies using genetically engineered mouse models revealed apoA-V to be a potent modulator of plasma TG. Knocking out apoA-V in mice resulted in a fourfold increase in plasma TG while overexp...

The effect of heritability and host genetics on the gut microbiota and metabolic syndrome

“…The regulatory role of APOA5 in triglyceride metabolism has been demonstrated extensively in mice and humans, especially in liver and plasma 18 50. Recently, a novel role of APOA5 in the gut was demonstrated in APOA5 -deficient mice—APOA5 regulates lymphatic transport of dietary lipids by modulating the production of chylomicrons in the gut 51. Based on the results of this recent study and our findings, it is likely that the gut environment of carriers of the minor allele of APOA5 SNP rs651821 is different from that of non-carriers in terms of quantity and types of lipids, which may lead to unfavourable conditions of gut ecology for the growth of Bifidobacterium .…”

Apolipoprotein A53'-UTR variants and cardiometabolic traits in Koreans: results from the Korean genome and epidemiology study and the Korea National Health and Nutrition Examination Survey

“…It was observed that the minor C allele in APOA5 rs651821, which increases circulating TG levels and MetS incidence, was significantly associated with reduced abundance of Bifidobacterium and its parent taxon Actinobacteria, independent of the individual's MetS status [ 31 ]. ApoA5 is known to be produced mainly in the liver but is also expressed at a low level in the intestine, and its function is to modulate chylomicron production [ 33 34 ]. Therefore, carriers of the minor C allele of APOA5 rs651821 have different lipid properties in the gut compared with non-carriers, which may lead to alteration of gut microbiota composition as mentioned above [ 31 ], suggesting a role for microbiome pattern in the regulation of ApoA5.…”

High density lipoprotein promotes nascent apolipoprotein A-V secretion from mRNA transfected cells

“…It is worth considering that this property may constitute an intrinsic design feature of apoA-V, thereby allowing for retention of apoA-V by cells under certain conditions, such as following partial hepatectomy wherein apoA-V mRNA is strongly upregulated [20]. Moreover, this aspect of apoA-V trafficking may be relevant to its known occurrence as a component of bile [7,8]. The finding that apoA-V levels in bile increase in response to dietary lipid intake suggest a regulated mechanism exists to control apoA-V delivery / entry to bile.…”

“…At the same time, cell associated apoA-V has been shown to associate with cytosolic lipid droplets (LD) [6]. In addition, apoA-V has been identified as an inducible component of bile [7,8]. To date, the molecular basis for the unusual distribution of apoA-V between these tissue compartments remains poorly understood.…”