A role for phosphatidylcholine and phosphatidylethanolamine in hepatic insulin signaling

Veen, Jelske N. van der; Lingrell, Susanne; McCloskey, Nicholas; LeBlond, Nicholas D.; Galleguillos, Danny; Zhao, Yuan; Curtis, Jonathan M.; Sipione, Simonetta; Fullerton, Morgan D.; Vance, Dennis E.; Jacobs, René L.

doi:10.1096/fj.201802117r

Cited by 51 publications

(26 citation statements)

References 53 publications

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“…2C, D and 3D, E) independent of adiposity. In agreement, we have recently demonstrated that insulin signaling is improved in primary hepatocytes and hepatoma cells that lack PEMT, which was linked to a decrease in the PC:PE molar ratio or an increase in PE (9).…”

Section: Pemt Deficiency Promotes Insulin Sensitivity Independent Of supporting

confidence: 85%

“…Lack of PEMT reduces the hepatic PC:PE molar ratio, impairing membrane integrity and leading to endoplasmic reticulum (ER) stress and liver disease (3,4,(6)(7)(8). Interestingly, the reduction in the hepatic PC:PE molar ratio is also associated with an improvement in hepatic insulin sensitivity in primary hepatocytes of Pemt 2/2 mice, suggesting that the protection against IR is independent of obesity and the development of NAFLD (9).…”

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confidence: 99%

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Hepatic PEMT activity mediates liver health, weight gain, and insulin resistance

Wan¹,

Veen²,

N'Goma³

et al. 2019

FASEB j.

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Phosphatidylethanolamine (PE) N‐methyltransferase (PEMT) accounts for ∼30% of hepatic phosphatidylcholine (PC) biosynthesis. Pemt−/− mice fed a high‐fat diet are protected against diet‐induced obesity (DIO) and insulin resistance (IR) but develop nonalcoholic fatty liver disease (NAFLD) associated with a decreased POPE ratio. We investigated whether the lack of hepatic PEMT or the lack of PEMT in other tissues (where it is expressed at low levels) is responsible for or contributes to the protection against DIO and IR in Pemt−/− mice. Furthermore, we investigated whether decreasing PEMT expression with antisense oligonucleotides (ASOs) would result in metabolic benefits in both lean and obese mice without negatively impacting liver health. We both restored hepatic PEMT in Pemt−/− mice via adeno‐associated virus delivery and decreased hepatic PEMT with ASOs in wild‐type and ob/ob mice. Weight gain, insulin sensitivity, and indices of liver function were determined. We report that the protection against DIO and IR and the development of NAFLD is dependent on hepatic PEMT activity. NAFLD, associated with a significant decrease in the hepatic PC:PE ratio, was exacerbated by PEMT deficiency in obese mice, suggesting that phospholipid insufficiency promotes NAFLD progression during obesity or overnutrition. Hepatic PEMT is critical for maintaining phospholipid balance, which is crucial for a healthy liver.—Wan, S., van der Veen, J. N., Bakala N'Goma, J.‐C., Nelson, R. C., Vance, D. E., Jacobs, R. L. Hepatic PEMT activity mediates liver health, weight gain, and insulin resistance. FASEB J. 33, 10986–10995 (2019). http://www.fasebj.org

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Section: Pemt Deficiency Promotes Insulin Sensitivity Independent Of supporting

confidence: 85%

mentioning

confidence: 99%

Hepatic PEMT activity mediates liver health, weight gain, and insulin resistance

Wan¹,

Veen²,

N'Goma³

et al. 2019

FASEB j.

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“…Consistent with our findings, several studies have also reported elevated lysine and PE levels in T2DM patients with glucose intolerance, insulin resistance and obesity . Increased plasma stearic acid, which could promote insulin resistance, inflammation, and obesity, is a potential predictor of diabetes in obesity .…”

Section: Discussionsupporting

confidence: 92%

Wulingsan (Oryeongsan/Goreisan) ameliorate lipid metabolism of obesity rats via regulation of the plasma metabolic profiling

Xue

Xue²,

Cui

et al. 2019

Biotech and App Biochem

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Objectives: Wulingsan has been used to cure disease about disorders related to fluid balance for thousands of years. The clinical practice of modern Chinese medicine has found that Wulingsan has the effect on reducing weight and fat, but its mechanism is not clear. This study investigated its effects on obesity rats and explored the underlying mechanisms by analyzing the plasma metabolic profiling. Methods: The effects of Wulingsan on obesity were evaluated with obesity rats induced by high-fat diet. Ultra high performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UPLC-Q-TOF/MS) was performed to discover potential biomarkers and evaluate whether Wulingsan could regulate these biomarkers. The levels of triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL-C), and low-density lipoprotein (LDL-C) in serum were assessed by ELISA kits. Results: Remarkably, TG, TC, HDL-C and LDL-C in obesity rats were ameliorated after oral administration of Wulingsan. Further investigation indicated that the plasma metabolic profiles were clearly improved. Twelve potential biomarkers were identified. After intervention, these biomarkers turned back to normal level at some extent. Conclusion: The results showed that Wulingsan extract groups were normalized. Additionally, this study also showed that the metabonomics method was a promising tool to unravel how traditional Chinese medicines worked and these data can provide scientific basis for clinical application of Wulingsan.

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“…(36) Importantly, it has been described that treatments to reduce the PC-to-PE ratio in the liver protect against the development of hepatic insulin resistance. (37) LysoPC is a death effector in the lipoapoptosis of hepatocytes. (38) In NASH, the diacylglycerol (DAG) that is normally consumed to produce PEs by the CDP-ethanolamine pathway is instead converted to TGs, promoting LD formation.…”

Section: Discussionmentioning

confidence: 99%

Ablation of Hmgb1 in Intestinal Epithelial Cells Causes Intestinal Lipid Accumulation and Reduces NASH in Mice

Gaskell

Désert

et al. 2019

Hepatol Commun

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Nonalcoholic steatohepatitis (NASH) is a metabolic disorder in which poor nutrition and the gut-to-liver interaction play a major role. We previously established that hepatic high mobility group box-1 (HMGB1) is involved in chronic liver disease. HMGB1 increases in patients with NASH and it is expressed in intestinal epithelial cells (IEC); yet, the role of intestinal HMGB1 in the pathogenesis of NASH has not been investigated. Thus, we hypothesized that IECderived HMGB1 could play a role in NASH due to local effects in the intestine that govern hepatic steatosis. Control littermates and Hmgb1 ΔIEC mice were fed for 1 or 24 weeks a control diet or a high fat, high cholesterol (CHO) and fructose-enriched diet (HFCFD). Hepatic and intestinal injury were analyzed. Hmgb1 ΔIEC mice were protected from HFCFD-induced NASH after 1 or 24 weeks of feeding; however, they showed extensive atypical lipid droplet accumulation and increased concentrations of triglycerides (TG) and CHO in jejunal IEC together with lower TG and other lipid classes in serum. Olive oil or CHO gavage resulted in decreased serum TG and CHO in Hmgb1 ΔIEC mice, respectively, indicating delayed and/or reduced chylomicron (CM) efflux. There was significant up-regulation of scavenger receptor class B type 1 (SR-B1) and down-regulation of apolipoprotein B48 (ApoB48) proteins, suggesting decreased lipid packaging and/or CM formation that resulted in lesser hepatosteatosis. Conclusion: Ablation of Hmgb1 in IEC causes up-regulation of SR-B1 and down-regulation of ApoB48, leads to lipid accumulation in jejunal IEC, decreases CM packaging and/or release, reduces serum TG, and lessens liver steatosis, therefore protecting Hmgb1 ΔIEC mice from HFCFD-induced NASH. (Hepatology Communications 2020;4:92-108). K ey features of nonalcoholic fatty liver disease (NAFLD) are steatosis and inflammation occurring in the absence of alcohol abuse. In about 20% of patients, simple fatty liver progresses to nonalcoholic steatohepatitis (NASH), identified by the presence of significant necroinflammatory activity and fibrosis. Unfortunately, NASH can progress to cirrhosis and increases the risk of developing hepatocellular carcinoma. The molecular mechanisms responsible for the onset of NAFLD and its progression to NASH are still not fully understood. Therefore, identification of targets that

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A role for phosphatidylcholine and phosphatidylethanolamine in hepatic insulin signaling

Cited by 51 publications

References 53 publications

Hepatic PEMT activity mediates liver health, weight gain, and insulin resistance

Hepatic PEMT activity mediates liver health, weight gain, and insulin resistance

Wulingsan (Oryeongsan/Goreisan) ameliorate lipid metabolism of obesity rats via regulation of the plasma metabolic profiling

Ablation of Hmgb1 in Intestinal Epithelial Cells Causes Intestinal Lipid Accumulation and Reduces NASH in Mice

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