Insufficiency of phosphatidylethanolamine N-methyltransferase is risk for lean non-alcoholic steatohepatitis

Nakatsuka, Atsuko; Matsuyama, Makoto; Yamaguchi, Satoshi; Katayama, Akihiro; Eguchi, Jun; Murakami, Kazutoshi; Teshigawara, Sanae; Ogawa, Daisuke; Wada, Nozomu; Yasunaka, Tetsuya; Ikeda, Fusao; Takaki, Akinobu; Watanabe, E.; Wada, Jun

doi:10.1038/srep21721

Cited by 45 publications

(44 citation statements)

References 51 publications

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“…35 Finally, a recent study on animal models hypothesized that a deficiency of the phosphatidylethanolamine Nmethyltransferase (PEMT) could play a key role in the development of NASH in lean individuals. 36 PEMT is an enzyme involved in the synthesis of phosphatidylcholines in liver cells. PEMT À/À mice on high fat-high sucrose diet did not develop obesity or insulin resistance compared with the PEMT þ/þ and presented normal cholesterol and triglyceride levels.…”

Section: Genetic and Environmental Factorsmentioning

confidence: 99%

“…A correlation with lower BMI has been also reported, suggesting that PEMT deficiency could be an etiologic agent of lean NASH. 36 Insulin resistance in adipose tissue develops early during fetal growth restriction and is maintained during the neonatal period and adulthood. 37 Besides genetic factors, intrauterine growth might play a role in favoring NAFLD, particularly in children.…”

Section: Genetic and Environmental Factorsmentioning

confidence: 99%

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NASH in Lean Individuals

Younes¹,

Bugianesi²

2019

Semin Liver Dis

175

151

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Nonalcoholic fatty liver disease (NAFLD) is generally associated with obesity and the related comorbidities but it can also develop in subjects with a body mass index (BMI) within the ethnic-specific cutoff of 25 kg/m2 BMI in Caucasian and 23 kg/m2 in Asian subjects, the so-called “lean” NAFLD. This sub-phenotype of NAFLD patients has been described across populations of different ethnicity, particularly in Asia, but it can be diagnosed in 10 to 20% of nonobese Americans and Caucasians. Pathophysiological mechanisms underpinning the “lean” phenotype are not completely understood, but they may include a more dysfunctional fat (visceral obesity, differences in adipocyte differentiation and altered lipid turnover), altered body composition (decreased muscle mass), a genetic background, not limited to patatin-like phospholipase domain-containing protein 3 (PNPLA3) C > G polymorphisms, epigenetic changes occurring early in life and a different pattern of gut microbiota. Lean subjects with NAFLD have milder features of the metabolic syndrome when compared with obese patients. Nonetheless they have a higher prevalence of metabolic alterations (e.g., dyslipidemia, arterial hypertension, insulin resistance, and diabetes) compared with healthy controls. Data on histological severity are controversial, but they can develop the full spectrum of liver disease associated with nonalcoholic steatohepatitis NASH. Since lean NAFLD usually present with less obesity-related comorbidities, it is commonly believed that this group would follow a relatively benign clinical course but recent data challenge this concept. Here, the authors describe the current knowledge about NAFLD in lean individuals and highlight the unanswered questions and gaps in the field.

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Section: Genetic and Environmental Factorsmentioning

confidence: 99%

Section: Genetic and Environmental Factorsmentioning

confidence: 99%

NASH in Lean Individuals

Younes¹,

Bugianesi²

2019

Semin Liver Dis

175

151

View full text Add to dashboard Cite

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“…107 Another relevant correlation is that insufficiency of phosphatidylethanolamine N-methyltransferase (PEMT) increases the risk of NASH in lean individuals. 108…”

Section: Key Pointsmentioning

confidence: 99%

Non-alcoholic fatty liver disease in lean individuals

Chowdhury²,

2019

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Non-alcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease, encompassing a spectrum from non-alcoholic fatty liver to non-alcoholic steatohepatitis, which can progress to cirrhosis. It has recently been recognised that NAFLD also occurs in individuals who are not obese, especially in Asian populations. In these patients, NAFLD manifests at lower overall body mass index thresholds in the presence of increased visceral adipose tissue. Currently, the principles of clinical management are similar to those in obese individuals, although, in specific regions and clinical situations, unique aetiologies of NAFLD must be treated specifically.

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“…Lastly, DG is converted to PC by CEPT1 and choline phosphotransferase 1 ( Chpt1 ), or converted to phosphatidylethanolamine (PE) by Cept1 and ethanolaminephosphotransferase 1 ( Ept1 ). PE is further converted to PC by phosphatidylethanolamine N-methyltransferase ( Pemt ), which is reported to play an important role in NASH development [23]. Among these enzymes related to DG utilization, the levels of Cept1 mRNA were increased in MCD-fed Gadd45a -null mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

Growth arrest and DNA damage-inducible 45α protects against nonalcoholic steatohepatitis induced by methionine- and choline-deficient diet

Tanaka

Takahashi

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Growth arrest and DNA damage-inducible 45 α (Gadd45α) is a stress-inducible protein that plays an important role in cell survival/death and DNA repair, but its contribution to the development of nonalcoholic steatohepatitis (NASH) has not been investigated. C57BL/6 Gadd45a-null and wild-type (WT) mice were treated with methionine- and choline-deficient diet (MCD) for eight weeks and phenotypic changes examined. Gadd45a-null mice had more severe hepatic inflammation and fibrosis, higher levels of mRNAs encoding pro-inflammatory, pro-fibrotic, and pro-apoptotic proteins, and greater oxidative and endoplasmic reticulum (ER) stress compared with WT mice. Indeed, Gadd45a mRNA was induced in response to ER stress in primary hepatocytes. Lipidomic analysis of NASH livers demonstrated decreased triacylglycerol (TG) in MCD-treated Gadd45a-null mice, which was presumably associated with increased mRNAs encoding phospholipase D (Pld1/2), phosphatidic acid phosphatase type 2A, and choline/ethanolaminephosphotransferase 1 (Cept1), involved in the phosphatidylcholine-phosphatidic acid-diacylglycerol cycle, and decreased mRNAs encoding fatty acid (FA)-binding protein 1 (Fabp1) and FA transport protein 5. Treatment of cultured primary hepatocytes with tumor necrosis factor α, transforming growth factor β, and hydrogen peroxide led to the corresponding induction of Fabp1, Pld1/2, and Cept1 mRNAs. Collectively, Gadd45α plays protective roles against MCD-induced NASH likely due to attenuating cellular stress and ensuing inflammatory signaling. These results also suggest an interconnection between hepatocyte injury, inflammation and disrupted glycerophospholipid/FA metabolism that yields a possible mechanism of decreased TG accumulation with NASH progression (i.e., “burned-out” NASH).

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Insufficiency of phosphatidylethanolamine N-methyltransferase is risk for lean non-alcoholic steatohepatitis

Cited by 45 publications

References 51 publications

NASH in Lean Individuals

NASH in Lean Individuals

Non-alcoholic fatty liver disease in lean individuals

Growth arrest and DNA damage-inducible 45α protects against nonalcoholic steatohepatitis induced by methionine- and choline-deficient diet

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