Lipoapoptosis induced by saturated free fatty acids stimulates monocyte migration: a novel role for Pannexin1 in liver cells

Xiao, Feng; Waldrop, Shar L.; Bronk, Steve F.; Gores, Gregory J.; Davis, Laurie S.; Kilic, Gordan

doi:10.1007/s11302-015-9456-5

Cited by 27 publications

(28 citation statements)

References 59 publications

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“…Other studies suggest that increased free fatty acids can induce hepatic lipoapoptosis, a major step in the pathogenesis in NASH, through c‐Jun N‐terminal kinase (JNK) activation . JNK activation can stimulate migration of monocytes into the liver, further causing hepatic inflammation and NASH . To extend further, the role of triglycerides as a treatment target has not been fully explored.…”

Section: Discussionmentioning

confidence: 99%

Histological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients

et al. 2017

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Although nonalcoholic fatty liver disease (NAFLD) is closely linked to obesity, around 10%-20% of nonobese Americans and Asians still develop NAFLD. Data on this special group are limited. We therefore studied the severity and clinical outcomes of nonobese NAFLD patients. Consecutive NAFLD patients who underwent liver biopsy were prospectively recruited. We used the NASH Clinical Research Network system to score the histology. The Asian body mass index cutoff of 25 kg/m 2 was used to define nonobese NAFLD. Among 307 recruited NAFLD patients, 72 (23.5%) were nonobese. Compared to obese patients, nonobese patients had lower NAFLD activity score (3.3 6 1.3 vs. 3.8 6 1.2; P 5 0.019), mainly contributed by steatosis (1.7 6 0.8 vs. 2.0 6 0.8; P 5 0.014) and presence of hepatocyte ballooning (60.9% vs. 73.4%; P 5 0.045). Similarly, nonobese patients had lower fibrosis stage (1.3 6 1.5 vs. 1.7 6 1.4; P 5 0.004), serum cytokeratin-18 fragments (283 vs. 404 U/L; P < 0.001) and liver stiffness measurement by transient elastography (6.3 vs. 8.6 kilopascals; P < 0.001). By multivariate analysis in nonobese patients, only elevated serum triglyceride level was independently associated with higher NAFLD activity score (adjusted odds ratio [OR], 1.644; P 5 0.021), whereas elevated creatinine level was the only factor associated with advanced fibrosis (adjusted OR, 1.044; P 5 0.025). After a median follow-up of 49 months, 6 patients died, 2 developed hepatocellular carcinoma, and 1 had liver failure, all of whom were in the obese group. Conclusion: Nonobese NAFLD patients tend to have less-severe disease and may have a better prognosis than obese patients. Hypertriglyceridemia and higher creatinine are the key factors associated with advanced liver disease in nonobese patients. (HEPATOLOGY 2017;65:54-64) SEE EDITORIAL ON PAGE 4 N onalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in the world. (1) It can progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). (2,3) Furthermore, patients with NAFLD have increased risk of cardiovascular events, other malignancies, and mortality. (4) NAFLD is strongly associated with obesity, metabolic syndrome (MetS), and cardiovascular risk factors and is more common in obese patients. (5,6) Nonetheless, a smaller, but significant, proportion of patients develop NAFLD despite having a relatively normal body mass Abbreviations: BMI, body mass index; CK-18, cytokeratin-18; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HDL, high-density lipoprotein; IQR, interquartile range; JNK, c-Jun N-terminal kinase; kPa, kilopascals; LSM, liver stiffness measurement; MetS, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD Activity Score; NASH, nonalcoholic steatohepatitis; OR, odds ratio; PNPLA3, patatin-like phospholipase domain-containing protein 3; PPV, positive predictive value; TE, transient elastography; TM6SF2, transmembrane 6 superfamily antigen 2.

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Section: Discussionmentioning

confidence: 99%

Histological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients

et al. 2017

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“…This process is mainly mediated by the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor 2 (TRAIL-R2), also known as death receptor 5 TRAIL-R2 especially contributes to cell death caused by palmitic acid, which induces downstream activation of caspase 8 and executionary caspases 3 and 7 [42,43]. Moreover, FFA-induced lipo-apoptosis in hepatocytes stimulate the release of ATP, which stimulate migration of monocytes [44]. In addition to hepatocytes, NPCs are also impacted by the toxic lipid accumulation.…”

Section: Hepatocyte Cell Death and Apoptosismentioning

confidence: 99%

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Roehlen

Crouchet

Baumert

2020

Cells

756

440

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Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver injury and disease-specific cell responses, the progression of fibrotic liver disease follows shared patterns across the main liver disease etiologies. Scientific discoveries within the last decade have transformed the understanding of the mechanisms of liver fibrosis. Removal or elimination of the causative agent such as control or cure of viral infection has shown that liver fibrosis is reversible. However, reversal often occurs too slowly or too infrequent to avoid life-threatening complications particularly in advanced fibrosis. Thus, there is a huge unmet medical need for anti-fibrotic therapies to prevent liver disease progression and HCC development. However, while many anti-fibrotic candidate agents have shown robust effects in experimental animal models, their anti-fibrotic effects in clinical trials have been limited or absent. Thus, no approved therapy exists for liver fibrosis. In this review we summarize cellular drivers and molecular mechanisms of fibrogenesis in chronic liver diseases and discuss their impact for the development of urgently needed anti-fibrotic therapies.

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“…Besides driving the inflammasome, Panx1 contributes to pathophysiological adenosine triphosphate release in lipo‐apoptosis induced by saturated fatty acids. In turn, this is capable of stimulating migration of human monocytes in vitro and may participate in the recruitment of monocytes in acute and/or chronic liver injury . Thus, Panx1‐based channels may play a role in hepatic inflammation by mediating an increase in extracellular adenosine triphosphate levels in lipotoxic liver injury.…”

Section: Pathophysiology Of Connexin and Pannexin (Hemi)channelsmentioning

confidence: 99%

Connexin and Pannexin (Hemi)Channels: Emerging Targets in the Treatment of Liver Disease

et al. 2019

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Connexin proteins are the building blocks of hemichannels, which dock further between adjacent cells to form gap junctions. Gap junctions control the intercellular exchange of critical homeostasis regulators. By doing so, gap junctions control virtually all aspects of the hepatic life cycle. In the last decade, it has become clear that connexin hemichannels also provide a pathway for cellular communication on their own independent of their role as structural precursors of gap junctions, namely between the cytosol of an individual cell and its extracellular environment. In contrast to gap junctions, connexin hemichannels become particularly active in liver disease by facilitating inflammation and cell death. This equally holds true for cellular channels composed of pannexins, being connexin‐like proteins recently identified in the liver that gather in structures reminiscent of hemichannels. This paper gives an overview of the involvement of connexin‐based and pannexin‐based channels in noncancerous liver disease.

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Lipoapoptosis induced by saturated free fatty acids stimulates monocyte migration: a novel role for Pannexin1 in liver cells

Cited by 27 publications

References 59 publications

Histological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients

Histological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Connexin and Pannexin (Hemi)Channels: Emerging Targets in the Treatment of Liver Disease

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