Cooperative stimulation of atherogenesis by lipopolysaccharide and palmitic acid-rich high fat diet in low-density lipoprotein receptor-deficient mice

Lu, Zhongyang; Li, Yanchun; Brinson, Colleen W.; Lopes‐Virella, Maria F.; Huang, Yan

doi:10.1016/j.atherosclerosis.2017.09.008

Cited by 14 publications

(13 citation statements)

References 50 publications

(50 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When both LPS and SFA in circulation are elevated, they may act in concert to boost a strong proinflammatory response that cannot be generated by LPS or SFA alone. Indeed, our recent study supported the above notion as it showed a cooperative stimulation of atherogenesis by combining treatment of LPS with feeding SFA-rich HFD in animal models [ 7 ]. Our in vitro study also showed that palmitic acid (PA), the most abundant SFA in plasma [ 8 ], amplified LPS-triggered signaling for upregulating proinflammatory genes such as interleukin 6 (IL-6) in macrophages [ 9 ].…”

Section: Introductionmentioning

confidence: 61%

Docosahexaenoic acid antagonizes the boosting effect of palmitic acid on LPS inflammatory signaling by inhibiting gene transcription and ceramide synthesis

Jin

et al. 2018

PLoS ONE

Self Cite

View full text Add to dashboard Cite

It is well known that saturated fatty acids (SFAs) and unsaturated fatty acid, in particular omega-3 polyunsaturated fatty acids (n-3 PUFAs), have different effects on inflammatory signaling: SFAs are pro-inflammatory but n-3 PUFAs have strong anti-inflammatory properties. We have reported that palmitic acid (PA), a saturated fatty acid, robustly amplifies lipopolysaccharide (LPS) signaling to upregulate proinflammatory gene expression in macrophages. We also reported that the increased production of ceramide (CER) via sphingomyelin (SM) hydrolysis and CER de novo synthesis plays a key role in the synergistic effect of LPS and PA on proinflammatory gene expression. However, it remains unclear if n-3 PUFAs are capable of antagonizing the synergistic effect of LPS and PA on gene expression and CER production. In this study, we employed the above macrophage culture system and lipidomical analysis to assess the effect of n-3 PUFAs on proinflammatory gene expression and CER production stimulated by LPS and PA. Results showed that DHA strongly inhibited the synergistic effect of LPS and PA on proinflammatory gene expression by targeting nuclear factor kappa B (NFκB)-dependent gene transcription. Results also showed that DHA inhibited the cooperative effect of LPS and PA on CER production by targeting CER de novo synthesis, but not SM hydrolysis. Furthermore, results showed that myriocin, a specific inhibitor of serine palmitoyltransferase, strongly inhibited both LPS-PA-stimulated CER synthesis and proinflammatory gene expression, indicating that CER synthesis is associated with proinflammatory gene expression and that inhibition of CER synthesis contributes to DHA-inhibited proinflammatory gene expression. Taken together, this study demonstrates that DHA antagonizes the boosting effect of PA on LPS signaling on proinflammatory gene expression by targeting both NFκB-dependent transcription and CER de novo synthesis in macrophages.

show abstract

Section: Introductionmentioning

confidence: 61%

Docosahexaenoic acid antagonizes the boosting effect of palmitic acid on LPS inflammatory signaling by inhibiting gene transcription and ceramide synthesis

Jin

et al. 2018

PLoS ONE

Self Cite

View full text Add to dashboard Cite

show abstract

“…The dose of LPS and the administration by weekly intraperitoneal injection were reported to be effective to induce atherosclerosis by the previous studies (26,52). We have also used this method in our published studies (21,22).…”

Section: Methodsmentioning

confidence: 98%

“…Therefore, it is important to elucidate the interaction between LPS and SFA on inflammation-associated diseases such as atherosclerosis and NASH. Recently, we reported that LPS and SFA cooperatively increased atherosclerosis in LDL receptordeficient (LDLR Ϫ/Ϫ ) mice, an animal model for human atherosclerosis (21). However, it remains largely unknown how the interaction between LPS and SFA affects hepatic inflammation, which is well known to contribute to atherosclerosis (48).…”

Section: Introductionmentioning

confidence: 99%

Saturated fatty acid combined with lipopolysaccharide stimulates a strong inflammatory response in hepatocytes in vivo and in vitro

et al. 2018

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

View full text Add to dashboard Cite

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and consumption of high-fat diet (HFD) is a risk factor for NAFLD. The HFD not only increases intake of saturated fatty acid (SFA), but also induces metabolic endotoxemia, a HFD-associated increase in circulating lipopolysaccharide (LPS). Although it is known that SFA or LPS promotes hepatic inflammation, a hallmark of NAFLD, it remains unclear how SFA in combination with LPS stimulates host inflammatory response in hepatocytes. In this study, we performed both in vivo and in vitro experiments to investigate the effect of SFA in combination with LPS on proinflammatory gene expression in hepatocytes. Our animal study showed that feeding low-density lipoprotein-deficient mice HFD enriched with SFA and injection of low dose LPS cooperatively stimulated IL-6 expression in livers. To understand how SFA and LPS interact to promote IL-6 expression, our in vitro studies showed that palmitic acid (PA), a major SFA, and LPS exerted synergistic effect on the expression of IL-6 in hepatocytes. Furthermore, co-culture of hepatocytes with macrophages resulted in a greater IL-6 expression than culture of hepatocytes without macrophages in response to the combination of PA and LPS. Finally, we observed that LPS and PA increased ceramide production by cooperatively stimulating ceramide de novo synthesis, which played an essential role in the synergistic stimulation of proinflammatory gene expression by LPS and PA. Taken together, this study showed that SFA in combination with LPS stimulated a strong inflammatory response in hepatocytes in vivo and in vitro.

show abstract

“…However, the mechanisms by which NASH is associated with CVDs have not been fully elucidated. Our study showed that feeding HP-HFD and administration of a low dose of LPS in LDLRϪ/Ϫ mice cooperatively induced not only NASH (24) but also atherosclerosis, the major cause of CVDs (28), suggesting that the HP-HFDfed LDLRϪ/Ϫ mice treated with a low dose of LPS are a good animal model to investigate the mechanisms whereby NASH is associated with atherosclerosis.…”

Section: Introductionmentioning

confidence: 66%

Amitriptyline inhibits nonalcoholic steatohepatitis and atherosclerosis induced by high-fat diet and LPS through modulation of sphingolipid metabolism

Syn

et al. 2020

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

View full text Add to dashboard Cite

We reported previously that increased acid sphingomyelinase (ASMase)-catalyzed hydrolysis of sphingomyelin, which leads to increases in ceramide and sphingosine 1 phosphate (S1P), played a key role in the synergistic upregulation of proinflammatory cytokines by palmitic acid (PA), a major saturated fatty acid, and lipopolysaccharide (LPS) in macrophages. Since macrophages are vital players in nonalcoholic steatohepatitis (NASH) and atherosclerosis, we assessed the effect of ASMase inhibition on NASH and atherosclerosis cooperatively induced by high-PA-containing high-fat diet (HP-HFD) and LPS in LDL receptor-deficient (LDLR−/−) mice. LDLR−/− mice were fed HP-HFD, injected with low dose of LPS and treated with or without the ASMase inhibitor amitriptyline. The neutral sphingomyelinase inhibitor GW4869 was used as control. Metabolic study showed that both amitriptyline and GW4869 reduced glucose, lipids, and insulin resistance. Histological analysis and Oil Red O staining showed that amitriptyline robustly reduced hepatic steatosis while GW4869 had modest effects. Interestingly, immunohistochemical study showed that amitriptyline, but not GW4869, strongly reduced hepatic inflammation. Furthermore, results showed that both amitriptyline and GW4869 attenuated atherosclerosis. To elucidate the underlying mechanisms whereby amitriptyline inhibited both NASH and atherosclerosis, but GW4869 only inhibited atherosclerosis, we found that amitriptyline, but not GW4869, downregulated proinflammatory cytokines in macrophages. Finally, we found that inhibition of sphingosine 1 phosphate production is a potential mechanism whereby amitriptyline inhibited proinflammatory cytokines. Collectively, this study showed that amitriptyline inhibited NASH and atherosclerosis through modulation of sphingolipid metabolism in LDLR−/− mice, indicating that sphingolipid metabolism in macrophages plays a crucial role in the linkage of NASH and atherosclerosis.

show abstract

Cooperative stimulation of atherogenesis by lipopolysaccharide and palmitic acid-rich high fat diet in low-density lipoprotein receptor-deficient mice

Cited by 14 publications

References 50 publications

Docosahexaenoic acid antagonizes the boosting effect of palmitic acid on LPS inflammatory signaling by inhibiting gene transcription and ceramide synthesis

Docosahexaenoic acid antagonizes the boosting effect of palmitic acid on LPS inflammatory signaling by inhibiting gene transcription and ceramide synthesis

Saturated fatty acid combined with lipopolysaccharide stimulates a strong inflammatory response in hepatocytes in vivo and in vitro

Amitriptyline inhibits nonalcoholic steatohepatitis and atherosclerosis induced by high-fat diet and LPS through modulation of sphingolipid metabolism

Contact Info

Product

Resources

About