Intestinal Lipid Handling

Abstract

Insulin resistance (IR) is the central feature of type 2 diabetes mellitus (T2D) and represents a major complication, commonly associated with atherogenic dyslipidemia. The latter is characterized by hypertriglyceridemia, elevated plasma very-low-density lipoprotein, reduced high-density lipoprotein (HDL), and presence of small, dense low-density lipoprotein (LDL).1 This atherogenic dyslipidemia is increasingly recognized as a postprandial phenomenon, 2 because postprandial triglyceride-rich lipoproteins (TRLs) and chylomicron remnants have been implicated as significant risk factors for atherosclerosis.3-5 Exaggerated hepatic very-low-density lipoprotein production and impaired plasma triglyceride clearance are thought to play a key role in this disorder. However, mounting evidence underlines the active implication of the small intestine in postprandial lipid alterations.It currently becomes clear that the small intestine is far from being a simple absorptive organ as it was previously thought. Indeed, recent studies have demonstrated that the small intestine regulates lipid metabolism in fed and fasting states and may, therefore, be central in lipid homeostasis in both normal physiology and pathophysiological conditions. 6-8 Lipid synthesis as well as lipoprotein assembly and secretion occur in this tissue, and these metabolic pathways are sensitive to several hormones such as insulin.9 Maintaining normal lipid homeostasis seems to require an interaction between intestinal and hepatic metabolism to adequately manage dietary intake. Otherwise, an imbalance in the lipid metabolism may lead to dyslipidemia and to increased risks of cardiovascular diseases (CVDs).Studies primarily on animal models (fructose-fed hamster; Psammomys obesus, JCR:LA-cp rat) have pointed out the © 2014 American Heart Association, Inc. Objective-Animal models have evidenced the role of intestinal triglyceride-rich lipoprotein overproduction in dyslipidemia. However, few studies have confronted this issue in humans and disclosed the intrinsic mechanisms. This work aimed to establish whether intestinal insulin resistance modifies lipid and lipoprotein homeostasis in the intestine of obese subjects. Approach and Results-Duodenal specimens obtained from 20 obese subjects undergoing bariatric surgery were paired for age, sex, and body mass index with or without insulin resistance, as defined by the homeostasis model assessment of insulin resistance. Insulin signaling, biomarkers of inflammation and oxidative stress, and lipoprotein assembly were assessed. The intestine of insulin-resistant subjects showed defects in insulin signaling as demonstrated by reduced protein kinase B phosphorylation and increased p38 mitogen-activated protein kinase phosphorylation, likely as the result of high oxidative stress (evidenced by malondialdehyde and conjugated dienes) and inflammation (highlighted by nuclear factor-κB, tumor necrosis factor-α, interleukin-6, intercellular adhesion molecule-1, and cyclooxygenase-2). Enhanced de novo lipogenesis rate and a...

Short Term Palmitate Supply Impairs Intestinal Insulin Signaling via Ceramide Production

“…Duodenal explants from insulinresistant obese subjects undergoing bariatric surgery were shown to express higher mRNA levels of free fatty acid-binding proteins and MTP and to secrete more intestinal triglyceriderich lipoproteins, i.e. chylomicrons (39). Interestingly, it has also been recently shown that bariatric surgery improves triglyceride-rich lipoprotein metabolism and, in particular, decreases the levels of intestinal lipoproteins in obese subjects (40).…”

Role of growth hormone-releasing hormone in dyslipidemia associated with experimental type 1 diabetes

“…Insulin influence in the intestine can reduce levels of ApoB48 and can stimulate lipoprotein lipase activity in control animals (50,51). However, oxidative stress, T1D, fructose feeding, and inflammation can each trigger dysregulation of intestinal insulin signaling and lipoprotein lipase deficiency, which can cause exaggerated lipogenesis and lipoprotein synthesis (28,29,50,51).…”

The Growing Problem of Obesity

“…Further, the authors found that evidence of abnormal cholesterol transport and metabolism, as suggested by reduced expression of the ATP-binding cassette A1 transporter and proprotein convertase subtilis/kexin type 9. Taken together, these findings from obese human duodenum suggested a mechanistic link between abnormal intestinal insulin signaling and atherogenic dyslipidemia 33 .…”