An ω-3-enriched diet alone does not attenuate CCl 4 -induced hepatic fibrosis

Harris, Todd R.; Kodani, Sean D.; Yang, Jun; Imai, Denise M.; Hammock, Bruce D.

doi:10.1016/j.jnutbio.2016.08.010

Cited by 9 publications

(13 citation statements)

References 52 publications

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“…Additionally, results of some experimental studies have raised alarms about the use of omega-3 PUFA in NASH and other hepatic diseases. In a mouse model of steatohepatitis, the effective incorporation of omega-3 PUFA in hepatocytes induced a more severe necro-inflammation and fibrosis of the liver respect to olive oil treatment [22] and a similar pro-fibrotic effect of omega-3 PUFA were demonstrated in mice treated with carbon tetrachloride [23] and in a rat model of biliary atresia [24].…”

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confidence: 80%

Omega-3 Polyunsaturated Fatty Acids in the Treatment of Non-Alcoholic Fatty Liver Disease: Are They So Good?

Colussi¹,

Soardo²,

Fagotto³

et al. 2017

J Metabolic Synd

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EditorialNon-alcoholic fatty liver disease (NAFLD) is the most prevalent hepatic problem in Western and Asian countries where it can affect more than 30% of people [1]. NAFLD pathological characteristic is a fat infiltration of the hepatocytes (hepatic steatosis) in subjects who are mild or no alcohol drinkers and do not have other secondary causes of hepatic lipid accumulation. In one fifth of affected patients, NAFLD can evolve in a liver inflammatory damage, which is associated with oxidative stress, cytolysis, and fibrosis (steatohepatitis) [2]. Of these patients, more than one-third progress to liver cirrhosis and a small part can develop hepatocarcinoma along years. It's not clear why some patients with NAFLD evolve to non-alcoholic steatohepatitis (NASH) while others remain stable over years, though a role of intestinal inflammation, gut dysbiosis, and hypovitaminosis D has been recently proposed [3]. Consistently, subjects at high risk to develop NAFLD are those affected by obesity, type 2 diabetes mellitus, and other conditions associated with insulin resistance or hyperinsulinemia such as hypertension, dyslipidemia, polycystic ovary disease, and metabolic syndrome, as well as patients with chronic inflammatory bowel diseases [4]. Patients with NAFLD are characterized by increased circulatory levels of triglycerides and free fatty acids (FFAs) that come from the adipose tissue through the lipolytic process, from the hepatic lipid de-novo synthesis, and to a minor extent from food intake. Both insulin resistance and hyperinsulinemia in predisposed subjects are associated with a visceral fat distribution and are responsible for the high level of circulatory FFAs [5]. FFAs enter and accumulate in insulin-resistant hepatocytes and by esterification with glycerol increase hepatic triglycerides synthesis and very low-density lipoproteins (VLDL) production; thus, favoring hypertriglyceridemia. The overflow of plasma lipids and lipid metabolites in non-adipose tissues induces "lipotoxicity", a pathological process characterized by lipids accumulation in liver and in other organs such as heart, kidney, pancreas, and skeletal muscle [6]. This process is responsible for the development and progression of heart and kidney failure, obesity, and diabetes, as well as for the systemic release of inflammatory cytokines. System cytokines maintain chronic subclinical inflammation, induce oxidative stress and endothelial dysfunction, and predispose to the atherosclerotic process [7]. Although NAFLD has been considered as the hepatic manifestation of the metabolic syndrome, evidence has shown that NAFLD is associated with cardiovascular morbidity and mortality independently of metabolic syndrome. Therefore, other than pro-cirrhotic, NAFLD had to be considered an important modifiable risk factor for cardiovascular diseases [8].As a result of the high clinical impact of NAFLD in the general population, treatment of NAFLD is essential. However, despite promising studies have been conducted with several agents, so far no strong...

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confidence: 80%

Omega-3 Polyunsaturated Fatty Acids in the Treatment of Non-Alcoholic Fatty Liver Disease: Are They So Good?

Colussi¹,

Soardo²,

Fagotto³

et al. 2017

J Metabolic Synd

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“…Mouse plasma (10 ml) was mixed with 50 ml of water containing 0.1% formic acid. The liquid-liquid extraction and LC-MS/MS analysis were performed as previously described (Harris et al, 2016).…”

Section: Methodsmentioning

confidence: 99%

“…Oxylipid Analysis. Oxylipids in the COX and lipoxygenase (LOX) branches of the arachidonic acid cascade were extracted and detected as described (Harris et al, 2016). Oxylipids in the P450 branch of the arachidonic acid cascade were detected as follows.…”

Section: Methodsmentioning

confidence: 99%

“…TPPU is a potent inhibitor of soluble epoxide hydrolase, an enzyme that metabolizes epoxy fatty acids (Rose et al, 2010). In previous studies, we have reported that TPPU treatment reduces hepatic fibrosis (Harris et al, 2015(Harris et al, , 2016. PTUPB contains the pharmacophores from both celecoxib and TPPU and inhibits both enzymes (Hwang et al, 2011).…”

Section: Celecoxib Modulates Carbon Tetrachloride Fibrosismentioning

confidence: 99%

“…We previously modulated the oxylipids in a CCl 4 -induced model of hepatic fibrosis through dietary manipulation of lipid intake as well as inhibition of sEH, which blocks the major route of metabolism of the EETs and other epoxy fatty acids (Harris et al, 2015(Harris et al, , 2016. In general, perturbation of the oxylipids with sEH inhibitors reduced collagen deposition in addition to the expression and activity of profibrotic matrix metalloproteases (MMPs) (Harris et al, 2015(Harris et al, , 2016. These results raised the question of how celecoxib, another modulator of oxylipids, would impact fibrosis in the CCl 4 model and whether the tools we developed for inhibiting both sEH and COX-2 would alter the observed effects of COX-2 inhibition.…”

Section: Introductionmentioning

confidence: 99%

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Celecoxib Does Not Protect against Fibrosis and Inflammation in a Carbon Tetrachloride–Induced Model of Liver Injury

et al. 2018

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The cyclooxygenase-2 (COX-2) selective inhibitor celecoxib is widely used in the treatment of pain and inflammation. Celecoxib has been explored as a possible treatment of liver fibrosis with contradictory results, depending on the model. The present study reports the effect of celecoxib in a 5-week carbon tetrachloride (CCl)-induced liver fibrosis mouse model. Celecoxib alone and in combination with inhibitors of the enzyme-soluble epoxide hydrolase (sEH), as well as a dual inhibitor that targets both COX-2 and sEH, were administered via osmotic minipump to mice receiving intraperitoneal injections of CCl Collagen deposition was elevated in the mice treated with both celecoxib and CCl compared with the control or CCl-only groups, as assessed by trichrome staining. Histopathology revealed more extensive fibrosis and cell death in the animals treated with both celecoxib and CCl compared with all other experimental groups. Although some markers of fibrosis, such as matrix metalloprotease, were unchanged or lowered in the animals treated with both celecoxib and CCl, overall, hepatic fibrosis was more severe in this group. Cotreatment with celecoxib and an inhibitor of sEH or treatment with a dual inhibitor of COX-2 and sEH decreased the elevated levels of fibrotic markers observed in the group that received both celecoxib and CCl Oxylipid analysis revealed that celecoxib reduced the level of prostaglandin E relative to the CCl only group. Overall, celecoxib treatment did not decrease liver fibrosis in CCl-treated mice.

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Lipidomic methodologies for biomarkers of chronic inflammation in nutritional research: ω-3 and ω-6 lipid mediators

Dasilva

Medina

2019

Free Radical Biology and Medicine

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The evolutionary history of hominins has been characterized by significant dietary changes, which include the introduction of meat eating, cooking, and the changes associated with plant and animal domestication. The Western pattern diet has been linked with the onset of chronic inflammation, and serious health problems including obesity, metabolic syndrome, and cardiovascular diseases. Diets enriched with ω-3 marine PUFAs have revealed additional improvements in health status associated to a reduction of proinflammatory ω-3 and ω-6 lipid mediators. Lipid mediators are produced from enzymatic and non-enzymatic oxidation of PUFAs. Interest in better understanding the occurrence of these metabolites has increased exponentially as a result of the growing evidence of their role on inflammatory processes, control of the immune system, cell signaling, onset of metabolic diseases, or even cancer. The scope of this review has been to highlight the recent findings on: a) the formation of lipid mediators and their role in different inflammatory and metabolic conditions, b) the direct use of lipid mediators as antiinflammatory drugs or the potential of new drugs as a new therapeutic option for the synthesis of antiinflammatory or resolving lipid mediators and c) the impact of nutritional interventions to modulate lipid mediators synthesis towards antiinflammatory conditions. In a second part, we have summarized methodological approaches (Lipidomics) for the accurate analysis of lipid mediators. Although several techniques have been used, most authors preferred the combination of SPE with LC-MS. Advantages and disadvantages of each method are herein addressed, as well as the main LC-MS difficulties and challenges for the establishment of new biomarkers and standardization of experimental designs, and finally to deepen the study of mechanisms involved on the inflammatory response.

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An ω-3-enriched diet alone does not attenuate CCl 4 -induced hepatic fibrosis

Cited by 9 publications

References 52 publications

Omega-3 Polyunsaturated Fatty Acids in the Treatment of Non-Alcoholic Fatty Liver Disease: Are They So Good?

Omega-3 Polyunsaturated Fatty Acids in the Treatment of Non-Alcoholic Fatty Liver Disease: Are They So Good?

Celecoxib Does Not Protect against Fibrosis and Inflammation in a Carbon Tetrachloride–Induced Model of Liver Injury

Lipidomic methodologies for biomarkers of chronic inflammation in nutritional research: ω-3 and ω-6 lipid mediators

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