Effects of high-fat diet on liver injury after small bowel resection

Onufer²,

Huang³

et al. 2020

Preprint

Self Cite

SummaryAssembly of high density lipoprotein (HDL) requires apoA1 and the cholesterol transporter ABCA1. Although the liver generates most HDL in blood, HDL synthesis also occurs in the small intestine. However, distinct functions for intestinal HDL are unknown. Here we show that HDL in the portal vein, which connects intestine to liver, derivesd mainly from intestine and potently neutralizes lipopolysaccharide (LPS). In a mouse model of short bowel syndrome where liver inflammation and fibrosis was driven by the LPS receptor TLR4, loss of intestine-derived HDL worsened liver injury, whereas liver status was improved by therapeutics that elevated and depended upon intestinal HDL production. Thus, protection of the liver from injury in response to gut-derived signals like LPS is a major function of intestinally synthesized HDL.

Section: Resultssupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Intestinal epithelium-derived high density lipoprotein restrains liver injury via the portal vein

Onufer²,

Huang³

et al. 2020

Preprint

Self Cite

“…To determine whether HDL neutralization of LPS modulates liver inflammation in vivo, we studied a model of small bowel resection that promotes marked liver fibrosis (27,28). Small bowel resection removed 50 or 75% of the small intestine (Fig.…”

Section: The Lps Receptor Tlr4 On Kcs Drives Liver Injury and Fibrosismentioning

confidence: 99%

“…For small bowel resection experiments, mice underwent a 50% proximal (jejunal) bowel resection, 75% proximal bowel resection, or sham control operation (bowel transection with reanastomosis alone), as previously described (28). In brief, through a midline laparotomy, the small bowel was exteriorized and transected 1-2 cm distal from the ligament of Treitz and ~12 cm (for 50% resection) or 6 cm (for 75% resection) proximal to the ileocecal junction.…”

Section: Small Bowel Surgery and Associated Treatments Or Transplantsmentioning

confidence: 99%

Enterically derived high-density lipoprotein restrains liver injury through the portal vein

Onufer

Huang

et al. 2021

Science

Self Cite

122

The biogenesis of high-density lipoprotein (HDL) requires apoA1 and the cholesterol transporter ABCA1. Although the liver generates most of the HDL in the blood, HDL synthesis also occurs in the small intestine. Here, we show that intestine-derived HDL traverses the portal vein in the HDL3 subspecies form, in complex with lipopolysaccharide (LPS)–binding protein (LBP). HDL3, but not HDL2 or low-density lipoprotein, prevented LPS binding to and inflammatory activation of liver macrophages and instead supported extracellular inactivation of LPS. In mouse models involving surgical, dietary, or alcoholic intestinal insult, loss of intestine-derived HDL worsened liver injury, whereas outcomes were improved by therapeutics that elevated and depended upon raising intestinal HDL. Thus, protection of the liver from injury in response to gut-derived LPS is a major function of intestinally synthesized HDL.

“…Perturbations in lymphatic function after SBR likely also contribute to greater delivery of luminal endotoxin into the portal vein, thereby contributing to liver injury 28 . Indeed, we have found severe liver injury and fibrosis in resected mice at 15 weeks following SBR when placed on a higher fat diet 29 . Liver injury and fibrosis are the most lethal clinical consequences of SBS 30 .…”

Section: Discussionmentioning

confidence: 87%

Lipid absorption and overall intestinal lymphatic transport are impaired following partial small bowel resection in mice

Onufer

Czepielewski

et al. 2022

Sci Rep

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Short bowel syndrome (SBS) is associated with diminished levels of serum fats caused by unknown mechanisms. We have shown that mesenteric lymphatics remodel to a more primitive state one week after small bowel resection (SBR); therefore, this study focuses on the effect of chronic lymphatic remodeling and magnitude of resection on intestinal lipid uptake and transport. C57BL6 and Prox1 creER-Rosa26LSLTdTomato (lymphatic reporter) mice underwent 50% or 75% proximal SBR or sham operations. Functional transport of lipids and fecal fat content was measured and lymphatic vasculature was compared via imaging. There was a significant reduction in functional transport of cholesterol and triglyceride after SBR with increasing loss of bowel, mirrored by a progressive increase in fecal fat content. We also describe significant morphological changes in the lymphatic vasculature in both the lamina propria and mesentery. Intestinal lymphatic drainage assay in vivo demonstrated a marked reduction of systemic absorption after resection. Intestinal lymphatic vessels significantly remodel in the setting of chronic SBS. This remodeling may account at least in part for impaired intestinal uptake and transport of fat via the compromised lymphatic architecture. We believe that these changes may contribute to the development of intestinal failure associated liver disease (IFALD), a major morbidity in patients with SBS.