TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis.

The MAP kinase kinase kinase TGFβ-activated kinase 1 (TAK1) is activated by TLRs, IL-1, TNF, and TGFβ and in turn activates IKK-NF-κB and JNK, which regulate cell survival, growth, tumorigenesis, and metabolism. TAK1 signaling also upregulates AMPK activity and autophagy. Here, we investigated TAK1-dependent regulation of autophagy, lipid metabolism, and tumorigenesis in the liver.

A TLR2/S100A9/CXCL-2 signaling network is necessary for neutrophil recruitment in acute and chronic liver injury in the mouse.

Background & Aims: Neutrophils are important immune effectors required for sterile and non-sterile inflammatory responses. However, neutrophils are associated with pathology in drug-induced liver injury, acute alcoholic liver disease, and ischemia-reperfusion injury. An understanding of the complex mechanisms that control neutrophil recruitment to the injured liver is desirable for developing strategies aimed at limiting neutrophil-mediated cellular damage.

Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3.

Chronic activation of mammalian target of rapamycin complex 1 (mTORC1) and p70 S6 kinase (S6K) in response to hypernutrition contributes to obesity-associated metabolic pathologies, including hepatosteatosis and insulin resistance. Sestrins are stress-inducible proteins that activate AMP-activated protein kinase (AMPK) and suppress mTORC1-S6K activity, but their role in mammalian physiology and metabolism has not been investigated. We show that Sestrin2--encoded by the Sesn2 locus, whose expression is induced upon hypernutrition--maintains metabolic homeostasis in liver of obese mice.

Anthrax toxin induces macrophage death by p38 MAPK inhibition but leads to inflammasome activation via ATP leakage.

Detection of microbial constituents by membrane associated and cytoplasmic pattern recognition receptors is the essence of innate immunity, leading to activation of protective host responses. However, it is still unclear how immune cells specifically respond to pathogenic bacteria. Using virulent and nonvirulent strains of Bacillus anthracis, we have shown that secretion of ATP by infected macrophages and the sequential activation of the P2X7 purinergic receptor and nucleotide binding oligomerization domain (NOD)-like receptors are critical for IL-1-dependent host protection from virulent B.

Oral docosapentaenoic acid (22:5n-3) is differentially incorporated into phospholipid pools and differentially metabolized to eicosapentaenoic acid in tissues from young rats.

The present study assessed the effect of oral supplementation with docosapentaenoic acid (DPA, 22:5n-3) on the levels of serum and tissue lipid classes and their fatty acid compositions including individual phospholipid types in rat liver, heart, and kidney. Sprague-Dawley rats received daily oral gavage over 10 days as corn oil without (controls) or with purified DPA in free fatty acid form (21.2 mg/day).

Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression.

Epidemiological studies indicate that overweight and obesity are associated with increased cancer risk. To study how obesity augments cancer risk and development, we focused on hepatocellular carcinoma (HCC), the common form of liver cancer whose occurrence and progression are the most strongly affected by obesity among all cancers. We now demonstrate that either dietary or genetic obesity is a potent bona fide liver tumor promoter in mice.

Protection of intestinal occludin tight junction protein by dietary gangliosides in lipopolysaccharide-induced acute inflammation.

Objectives: Intestinal permeability and barrier function are regulated by expression of tight junction proteins. Lipopolysaccharide (LPS), tumor necrosis factor-alpha, and interleukin-1beta induce expression of nitric oxide (NO) and reduce the expression of gut tight junction proteins. The purpose of this study was to determine whether dietary gangliosides (GGs) increase the concentration of the anti-inflammatory cytokine interleukin-10 (IL-10) in response to LPS, thereby inhibiting NO production and protecting gut occludin tight junction protein from degradation.

Postnatal dietary supplementation with either gangliosides or choline: effects on spatial short-term memory in artificially-reared rats.

This study addressed the hypothesis that dietary supplementation with either gangliosides or choline during the brain growth spurt would enhance short-term spatial memory. Male Long-Evans rats were reared artificially from postnatal days (PD) 5-18 and were fed diets containing either (i) choline chloride 1250 mg/l (CHL), (ii) choline chloride 250 mg/l and GD3 24 mg/l (GNG) or (iii) choline chloride 250 mg/l (STD). A fourth group (SCK) was reared normally.

Dietary ganglioside inhibits acute inflammatory signals in intestinal mucosa and blood induced by systemic inflammation of Escherichia coli lipopolysaccharide.

Our previous study demonstrated that feeding ganglioside increased total ganglioside content while decreasing cholesterol and caveolin-1 content in developing rat intestinal lipid microdomains. Cholesterol or caveolin depletion in membranes inhibits inflammatory signaling by disrupting microdomain structure. We hypothesized that dietary ganglioside-induced reduction in cholesterol content will reduce proinflammatory mediators in the intestinal mucosa after acute exposure to bacterial endotoxin.

Dietary gangliosides enhance in vitro lipid uptake in weanling rats.

Background: The intestine adapts morphologically or functionally in response to environmental stimuli. Dietary lipids modify brush border membrane (BBM) permeability and nutrient transporter activities. Gangliosides (GANG) are glycolipids in human milk that are present only in low amounts in infant formula.

Dietary gangliosides increase the content and molecular percentage of ether phospholipids containing 20:4n-6 and 22:6n-3 in weanling rat intestine.

This study was conducted to determine whether dietary ganglioside (GG) increases the content of ether phospholipids (EPL) in intestinal mucosa. Weanling Sprague-Dawley rats were fed a semipurified diet consisting of 20% fat as a control diet. Two experimental diets were formulated by adding either 0.

Dietary ganglioside and long-chain polyunsaturated fatty acids increase ganglioside GD3 content and alter the phospholipid profile in neonatal rat retina.

Purpose: During early development, the ganglioside composition of the retina changes significantly, in that GD3 becomes the primary ganglioside in the mammalian retina. Because gangliosides play an important role in neuronal cell differentiation and proliferation, this change in ganglioside profile may indicate retinal maturation. Dietary long-chain polyunsaturated fatty acids (LCPs) such as 20:4n-6 and 22:6n-3 improve visual acuity in infants.

Dietary ganglioside decreases cholesterol content, caveolin expression and inflammatory mediators in rat intestinal microdomains.

Membrane microdomains rich in cholesterol and sphingolipids, including gangliosides (GGs), are known to be important regions for cell signaling and binding sites for various pathogens. Cholesterol depletion inhibits the cellular entry of pathogens and also reduces inflammatory signals by disrupting microdomain structure. Our previous study showed that dietary gangliosides increased total ganglioside incorporation while decreasing cholesterol in the intestinal mucosa.

Diet-induced changes in membrane gangliosides in rat intestinal mucosa, plasma and brain.

Objectives: The objective of this study was to determine if dietary gangliosides induce changes in the ganglioside content of intestinal mucosa, plasma and brain and to identify where GM3 and GD3 are localized in the enterocyte membrane.

Methods: Male 18-day-old Sprague-Dawley rats were fed a semipurified diet containing 20% (w/w) fat. The control diet contained triglyceride, reflecting the fat formulation of an existing infant formula.

Fatty acid composition of serum phospholipid of premenopausal women and postmenopausal women receiving and not receiving hormone replacement therapy.

Objective: To compare the fatty acid composition of serum phospholipid of premenopausal women with that of postmenopausal women receiving and not receiving hormone replacement therapy (HRT).

Design: Women between the ages of 43 and 70 were recruited for two separate case-comparison studies. Participants were grouped as either premenopausal, postmenopausal receiving HRT, or postmenopausal not receiving HRT.

Fatty acid compositions of serum phospholipids of postmenopausal women: a comparison between Greenland Inuit and Canadians before and after supplementation with fish oil.

Objectives: We compared serum phospholipid fatty acid compositions, in particular the status of omega-3 polyunsaturated fatty acid (PUFA), of postmenopausal Greenland Inuit women and postmenopausal Canadian women at baseline and after supplementing the Canadian women with a fish-oil product.

Methods: Fasting serum samples were collected from 15 Inuit subjects from Greenland and 16 non-Inuit subjects from Canada. In addition, eight Canadian subjects provided fasting serum samples after completing a long-chain omega-3 PUFA intervention (2.