Inflammatory stress induces lipid accumulation in multi-organs of &amp;lt;italic&amp;gt;db&amp;lt;/italic&amp;gt;/&amp;lt;italic&amp;gt;db&amp;lt;/italic&amp;gt; mice

Ling, Kun; Zhang, Yang; Liu, Jing; Wu, Yu; Hu, Ze Bo; Liu, Liang; Liu, Bi Cheng

doi:10.1093/abbs/gmv079

Cited by 10 publications

(8 citation statements)

References 28 publications

(33 reference statements)

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“…Indeed, inflammatory stress is induced by lipid accumulation in multiple organs in mice (70), suggesting the reciprocal maintenance between immune homeostasis and lipid metabolism. Moreover, it has become increasingly clear that inflammation can lead to the exacerbation of immune and nonimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

Regulatory T cells suppress excessive lipid accumulation in alcoholic liver disease

Wang¹,

Wu²,

Wang³

et al. 2019

Journal of Lipid Research

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Sensitization of hepatic immune cells from chronic alcohol consumption gives rise to inflammatory accumulation, which is considered a leading cause of liver damage. Regulatory T cells (Tregs) are an immunosuppressive cell subset that plays an important role in a variety of liver diseases; however, data about pathological involvement of Tregs in liver steatosis of alcoholic liver disease (ALD) is insufficient. In mouse models of ALD, we found that increased lipid accumulation by chronic alcohol intake was accompanied by oxidative stress, inflammatory accumulation, and Treg decline in the liver. Adoptive transfer of Tregs relieved lipid metabolic disorder, oxidative stress, inflammation, and, consequently, ameliorated the alcoholic fatty liver. Macrophages are a dominant source of inflammation in ALD. Aberrant macrophage activation and cytokine production were activated during chronic alcohol consumption, but were significantly inhibited after Treg transfer. In vitro, macrophages were co-activated by alcohol and lipopolysaccharide to mimic a condition for alcoholic liver microenvironment. Tregs suppressed monocyte chemoattractant protein-1 and TNF-α production from these macrophages. However, such effects of Tregs were remarkably neutralized when interleukin (IL)-10 was blocked. Altogether, our data uncover a novel role of Tregs in restoring liver lipid metabolism in ALD, which partially relies on IL-10-mediated suppression of hepatic pro-inflammatory macrophages.

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Section: Discussionmentioning

confidence: 99%

Regulatory T cells suppress excessive lipid accumulation in alcoholic liver disease

Wang¹,

Wu²,

Wang³

et al. 2019

Journal of Lipid Research

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“…Since palmitate is the most abundant saturated FFA [56,57,58] that mainly increases during diabetes, both in humans and in experimental animal models [59], in this study we used it to mimic diabetic hyperlipidemia and insulin resistance in an in vitro model of intestinal L-cells. Our data are in agreement with previous reports that explored intestinal lipid accumulation in several metabolic disorders such as obesity and diabetes [60,61,62].…”

Section: Discussionsupporting

confidence: 94%

Chronic Exposure to Palmitate Impairs Insulin Signaling in an Intestinal L-cell Line: A Possible Shift from GLP-1 to Glucagon Production

Filippello

Urbano

Mauro

et al. 2018

IJMS

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Obesity and type 2 diabetes mellitus (T2DM) are characterized by insulin resistance and impaired glucagon-like peptide-1 (GLP-1) secretion/function. Lipotoxicity, a chronic elevation of free fatty acids in the blood, could affect insulin-signaling in many peripheral tissues. To date, the effects of lipotoxicity on the insulin receptor and insulin resistance in the intestinal L-cells need to be elucidated. Moreover, recent observations indicate that L-cells may be able to process not only GLP-1 but also glucagon from proglucagon. The aim of this study was to investigate the effects of chronic palmitate exposure on insulin pathways, GLP-1 secretion and glucagon synthesis in the GLUTag L-cell line. Cells were cultured in the presence/absence of palmitate (0.5 mM) for 24 h to mimic lipotoxicity. Palmitate treatment affected insulin-stimulated GLP-1 secretion, insulin receptor phosphorylation and IRS-1-AKT pathway signaling. In our model lipotoxicity induced extracellular signal-regulated kinase (ERK 44/42) activation both in insulin stimulated and basal conditions and also up-regulated paired box 6 (PAX6) and proglucagon expression (Gcg). Interestingly, palmitate treatment caused an increased glucagon secretion through the up-regulation of prohormone convertase 2. These results indicate that a state of insulin resistance could be responsible for secretory alterations in L-cells through the impairment of insulin-signaling pathways. Our data support the hypothesis that lipotoxicity might contribute to L-cell deregulation.

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“…Interestingly, SREBP-1a deletion in macrophages protected against LPS endotoxic shock through a blunted proinflammatory response (15), suggesting a direct effect of SREBP on regulating the immune response. Conversely, inflammatory stress increased SREBP-2 activation and lipid accumulation in the kidneys of diabetic mice (30), and SREBP1/2 activation in pulmonary alveolar cells increased lipid deposition and inflammation (33). Thus, whether SREBP activation in UUO is an early event leading to inflammation, or Fig.…”

Section: Discussionmentioning

confidence: 99%

SREBP inhibition ameliorates renal injury after unilateral ureteral obstruction

Mustafa

Wang

Chen

et al. 2016

American Journal of Physiology-Renal Physiology

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Tubulointerstitial fibrosis is a major feature associated with declining kidney function in chronic kidney disease of diverse etiology. No effective means as yet exists to prevent the progression of fibrosis. We have shown that the transcription factor sterol-regulatory element-binding protein 1 (SREBP-1) is an important mediator of the profibrotic response to transforming growth factor-β (TGF-β) and angiotensin II, both key cytokines in the fibrotic process. Here, we examined the role of SREBP in renal interstitial fibrosis in the unilateral ureteral obstruction (UUO) model. The two isoforms of SREBP (-1 and -2) were activated by 3 days after UUO, with SREBP-1 showing a more sustained activation to 21 days. We then examined whether SREBP1/2 inhibition with the small-molecule inhibitor fatostatin could attenuate fibrosis after 14 days of UUO. SREBP activation was confirmed to be inhibited by fatostatin. Treatment decreased interstitial fibrosis, TGF-β signaling, and upregulation of α-smooth muscle actin (SMA), a marker of fibroblast activation. Fatostatin also attenuated inflammatory cell infiltrate and apoptosis. Associated with this, fatostatin preserved proximal tubular mass. The significant increase in atubular glomeruli observed after UUO, known to correlate with irreversible renal functional decline, was also decreased by treatment. In cultured primary fibroblasts, TGF-β1 induced the activation of SREBP-1 and -2. Fatostatin blocked TGF-β1-induced α-SMA and matrix protein upregulation. The inhibition of SREBP is thus a potential novel therapeutic target in the treatment of fibrosis in chronic kidney disease.

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Inflammatory stress induces lipid accumulation in multi-organs of <italic>db</italic>/<italic>db</italic> mice

Cited by 10 publications

References 28 publications

Regulatory T cells suppress excessive lipid accumulation in alcoholic liver disease

Regulatory T cells suppress excessive lipid accumulation in alcoholic liver disease

Chronic Exposure to Palmitate Impairs Insulin Signaling in an Intestinal L-cell Line: A Possible Shift from GLP-1 to Glucagon Production

SREBP inhibition ameliorates renal injury after unilateral ureteral obstruction

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