Excess consumption of trans-fatty acid could increase the risk of non-alcoholic steatohepatitis (NASH); however, treatment targeting trans-fatty acid-induced NASH has not been examined. Here we focused on the influence of trans-fatty acid intake on endoplasmic reticulum (ER) stress in hepatocytes, so we investigated the effect of the chemical chaperone 4-phenylbutyric acid (PBA), on trans-fatty acid-caused steatohepatitis using diabetic KK-Ay mice. Elaidic acid (EA, trans-fatty acid) alone did not cause definitive liver injury. In contrast, EA plus low-dose fructose induced extensive apoptosis in hepatocytes with severe fat accumulation. EA plus fructose significantly increased ER stress markers such as glucose-regulated protein 78 (GRP78), eukaryotic initiation factor 2α (eIF2α) and phosphorylated c-jun N-terminal kinase (JNK), while PBA significantly reduced this response. In vitro, EA promoted expression of GRP78 and phosphorylation of eIF2α in primary-cultured hepatocytes. EA also increased hepatocellular susceptibility to low-dose tert-butyl hydroperoxide. Treatment with PBA significantly reduced these responses. In conclusion, EA potentiates susceptibly to non-hazardous dose of fructose, and increases ER and oxidative stress. PBA improved steatohepatitis induced by EA plus fructose through amelioration of ER stress. Therefore, ER stress-targeted therapy using a chemical chaperone is a promising novel strategy for trans-fatty acid-induced steatohepatitis.

Aim: Pharmacological treatment for metabolic syndromerelated non-alcoholic steatohepatitis has not been established. We investigated the effect of L-carnitine, an essential substance for β-oxidation, on metabolic steatohepatitis in mice. Methods:Male KK-A y mice were fed a high-fat diet (HFD) for 8 weeks, with supplementation of L-carnitine (1.25 mg/mL) in drinking water for the latter 4 weeks.Results: Serum total carnitine levels were decreased following HFD feeding, whereas the levels were reversed almost completely by L-carnitine supplementation. In mice given L-carnitine, exacerbation of hepatic steatosis and hepatocyte apoptosis was markedly prevented even though HFD feeding was continued. Body weight gain, as well as hyperlipidemia, hyperglycemia, and hyperinsulinemia, following HFD feeding were also significantly prevented in mice given L-carnitine. High-fat diet feeding elevated hepatic expression levels of carnitine palmitoyltransferase 1A mRNA; however, production of β-hydroxybutyrate in the liver was not affected by HFD alone.In contrast, L-carnitine treatment significantly increased hepatic β-hydroxybutyrate contents in HFD-fed mice. L-carnitine also blunted HFD induction in sterol regulatory element binding protein-1c mRNA in the liver. Furthermore, L-carnitine inhibited HFD-induced serine phosphorylation of insulin receptor substrate-1 in the liver. L-carnitine decreased hepatic free fatty acid content in 1 week, with morphological improvement of swollen mitochondria in hepatocytes, and increases in hepatic adenosine 5'-triphosphate content.Conclusions: L-carnitine ameliorates steatohepatitis in KK-A y mice fed an HFD, most likely through facilitating mitochondrial β-oxidation, normalizing insulin signals, and inhibiting de novo lipogenesis in the liver. It is therefore postulated that supplementation of L-carnitine is a promising approach for prevention and treatment of metabolic syndrome-related non-alcoholic steatohepatitis.

Seminomas rarely metastasize to the gastrointestinal tract. In general, these lesions metastasize to the lungs or retroperitoneal lymph nodes. A 34-year-old Japanese man who had undergone orchiectomy for seminoma two years earlier experienced shortness of breath and tarry stools. The patient presented at our hospital and was diagnosed with metastatic seminoma to the third portion of the duodenum on double balloon endoscopy. He was effectively treated with chemotherapy and continues to progress well, with no episodes of recurrence.

BackgroundThe prevalence of nonalcoholic fatty liver disease (NAFLD) and alcohol-associated/related liver disease (ALD) with metabolic syndrome is globally increasing. Metabolic syndrome and excessive alcohol consumption synergically exacerbate liver pathologies; therefore, drinking-speci c serum markers unaffected by liver injury or metabolic syndrome are essential to assess alcohol consumption. We evaluated the ratio of carbohydrate-de cient transferrin to total transferrin (%CDT) in patients with fatty liver disease, particularly focusing on its correlation with metabolic factors (UMIN000033550). MethodsA total of 120 patients with fatty liver disease, including ALD and NAFLD, were screened for alcohol misuse using the Alcohol Use Disorders Identi cation Test. Associations of metabolic syndrome-related factors and hepatic steatosis/liver stiffness with drinking markers such as %CDT, gamma-glutamyl transferase (GGT), and mean corpuscular volume (MCV) were assessed using multiple linear regression analyses. Results%CDT signi cantly increased with 3-4 drinks/day. The optimal cut-off value for identifying non-to light drinkers was 1.78% (sensitivity, 71.8%; speci city, 83.7%; area under the receiver operating characteristic curve [AUROC], 0.851), which was signi cantly higher than that for GGT. The cut-off value for identifying heavy drinkers was 2.08% (sensitivity, 65.5%; speci city, 86.8%; AUROC, 0.815). Multiple regression analysis revealed that this proportion was negatively correlated with body mass index, whereas GGT and MCV were in uenced by multiple factors involved in liver injury and dyslipidemia. Conclusions%CDT showed a strong correlation with alcohol consumption, independent of liver damage, steatosis/stiffness, or metabolic syndrome-related factors, indicating that it is a useful drinking marker for the accurate diagnosis of NAFLD and ALD.

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