Mechanism of Dyslipidemia in Obesity—Unique Regulation of Ileal Villus Cell Brush Border Membrane Sodium–Bile Acid Cotransport

Abstract

In obesity, increased absorption of dietary fat contributes to altered lipid homeostasis. In turn, dyslipidemia of obesity leads to many of the complications of obesity. Bile acids are necessary for the absorption of dietary fat. In the mammalian intestine, apical sodium-dependent bile acid cotransporter (ASBT; SLC10A2) is exclusively responsible for the reabsorption of bile acids in the terminal ileum. In rat and mice models of obesity and importantly in obese humans, ASBT was increased in ileal villus cells. The mechanism of stimulation of ASBT was secondary to an increase in ASBT expression in villus cell brush border membrane. The stimulation of ASBT was not secondary to the altered Na-extruding capacity of villus cells during obesity. Further, increased Farnesoid X receptor (FXR) expression in villus cells during obesity likely mediated the increase in ASBT. Moreover, enhanced FXR expression increased the expression of bile-acid-associated proteins (IBABP and OSTα) that are responsible for handling bile acids absorbed via ASBT in villus cells during obesity. Thus, this study demonstrated that in an epidemic condition, obesity, the dyslipidemia that leads to many of the complications of the condition, may, at least in part, be due to deregulation of intestinal bile acid absorption.

Neurotensin differentially regulates bile acid metabolism and intestinal FXR‐bile acid transporter axis in response to nutrient abundance

“…Human ileal ASBT and OSTα expression was significantly increased in obesity compared to non-obese conditions. 43 In our current study, however, we showed a clear trend for a decrease in the expression F I G U R E 3 HFD inhibits ileal Fxr and BA transporter expression which is upregulated in NT-deficient mice. Total RNA was isolated from ileal mucosal scrapings of male NT+/+ and NT −/− mice fed LFD or HFD for 5 weeks.…”

“…Sinal et al 20 provide convincing evidence showing undetectable ILBT mRNA in Fxr null mice under either control or CA diet. Human ileal ASBT and OSTα expression was significantly increased in obesity compared to non‐obese conditions 43 . In our current study, however, we showed a clear trend for a decrease in the expression of ileal Asbt, Ilbp, Ostα, and Ostβ in HFD‐fed NT +/+ mice at both the early stage and the later stage of obesity; consistent with the expression of Fxr, the expression of these genes also remained at relatively high levels in NT −/− mice fed HFD, indicating that NT contributed to HFD‐induced disruption of BA transporter signaling under obese conditions.…”

MiR-203 is an anti-obese microRNA by targeting apical sodium-dependent bile acid transporter

“…ASBT is considered an attractive target for the intervention of diseases related to BA, cholesterol, lipid, glucose, and so forth. Several studies have also reported an increase in the ASBT level in obesity ( Sundaram et al., 2019 ; van de Peppel et al., 2020 ). However, the upstream regulators that contribute to ASBT upregulation were nearly discovered.…”

Machine-learning-based integrative –‘omics analyses reveal immunologic and metabolic dysregulation in environmental enteric dysfunction

“… 20 Changes in the expression of ASBT have been linked to bile acid malabsorption in inflammatory bowel disease. 35 , 36 Further, studies have shown that bile acids in the colon may induce the secretion of water and electrolytes from the colon wall, leading to diarrhea. 37 Thus, ABST is increasingly becoming a target for pharmaceutical interventions in bile acid-related disorders and may be an avenue for EED therapy.…”