Increased gastrointestinal ethanol production in obese mice: Implications for fatty liver disease pathogenesis

Cope, Keary A.; Risby, Terence H.; Diehl, Anna Mae

doi:10.1053/gast.2000.19267

Cited by 318 publications

(215 citation statements)

References 45 publications

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“…With age, obese ob/ob mice develop intestinal bacterial overgrowth, 29 which increases portal endotoxemia and hepatic exposure to endogenous LPS. 30 This, in turn, promotes inflammatory cytokine production and steatohepatitis, because treating ob/ob mice with either probiotic (to modify their exposure to endogenous intestinal bacterial products) or anti-TNF-␣ antibodies (to inhibit TNF-␣ activity) significantly improves their steatohepatitis.…”

Section: Resultsmentioning

confidence: 99%

Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis

Oben

Yang

et al. 2004

Hepatology

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It is not known why natural killer T (NKT) cells, which modulate liver injury by regulating local cytokine production, are reduced in leptin-deficient ob/ob mice. NKT cells express adrenoceptors. Thus, we hypothesize that the low norepinephrine (NE) activity of ob/ob mice promotes depletion of liver NKT cells, thereby sensitizing ob/ob livers to lipopolysaccharide (LPS) toxicity. To evaluate this hypothesis, hepatic NKT cells were quantified in wild-type mice before and after treatment with NE inhibitors, and in dopamine ␤-hydroxylase knockout mice (which cannot synthesize NE) and ob/ob mice before and after 4 weeks of NE supplementation. Decreasing NE activity consistently reduces liver NKT cells, while increasing NE has the opposite effect. Analysis of hepatic and thymic NKT cells in mice of different ages demonstrate an age-related accumulation of hepatic NKT cells in normal mice, while liver NKT cells become depleted after birth in ob/ob mice, which have increased apoptosis of hepatic NKT cells. NE treatment inhibits apoptosis and restores hepatic NKT cells. In ob/ob mice with reduced hepatic NKT cells, hepatic T and NKT cells produce excessive T helper (Th)-1 proinflammatory cytokines and the liver is sensitized to LPS toxicity. NE treatment decreases Th-1 cytokines, increases production of Th-2 cytokines, and reduces hepatotoxicity. Studies of CD1d-deficient mice, which lack the receptor required for NKT cell development, demonstrate that they are also unusually sensitive to LPS hepatotoxicity. In conclusion, low NE activity increases hepatic NKT cell apoptosis and depletes liver NKT cells, promoting proinflammatory polarization of hepatic cytokine production that sensitizes the liver to LPS toxicity. (HEPATOLOGY 2004;40:434 -441.)

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Section: Resultsmentioning

confidence: 99%

Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis

Oben

Yang

et al. 2004

Hepatology

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“…1,2 Acute alcohol has been previously shown to attenuate inflammatory activation and to induce oxidative stress both acutely and chronically 22 Alcohol stimulation was also relevant because increased gastrointestinal ethanol production in ob/ob mice has been implicated in the pathogenesis of fatty liver disease. 23 Stimulation with either alcohol or LPS alone induced significantly higher IL-6 and TNF-␣ levels in ob/ob mice compared to lean littermates (Figs. 1.A and B).…”

Section: Opposite Regulation Of Serum Tnf-␣ and Il-6 Levels In Mice Wmentioning

confidence: 97%

Diverse regulation of NF-κB and peroxisome proliferator-activated receptors in murine nonalcoholic fatty liver

et al. 2004

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Fatty liver is highly sensitive to inflammatory activation. Peroxisome proliferator-activated receptors (PPAR) have anti-inflammatory effects and regulate lipid metabolism in the fatty liver. We hypothesized that fatty liver leads to endotoxin sensitivity through an imbalance between pro-and anti-inflammatory signals. Leptin-deficient, ob/ob mice and their lean littermates were challenged with single or double insults and pro-and anti-inflammatory pathways were tested on cytokine production and activation of nuclear regulatory factors NF-B and peroxisome proliferator receptor element (PPRE). Ob/ob mice produced significantly higher serum tumor necrosis factor ␣ (TNF-␣) and interleukin (

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“…Overall, these studies suggest that, endotoxemia is not required in the pathogenesis of NASH. Endotoxemia may contribute to disease progression in some NASH cases, but other challenges such as gut derived alcohol (39,41), endoplasmic reticulum stress, and adipose tissue derived threats may cause NASH independently from endotoxemia. Our observations highlight the current "multi-hit" hypothesis for the pathogenesis of NASH (69).…”

Section: Possible Roles Of Lps On Metabolic Diseases and Nafld/nash: mentioning

confidence: 99%

Gut microbiome and nonalcoholic fatty liver diseases

2014

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Increased gastrointestinal ethanol production in obese mice: Implications for fatty liver disease pathogenesis

Cited by 318 publications

References 45 publications

Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis

Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis

Diverse regulation of NF-κB and peroxisome proliferator-activated receptors in murine nonalcoholic fatty liver

Gut microbiome and nonalcoholic fatty liver diseases

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