Low-dose benzo[a]pyrene exposure induces hepatic lipid deposition through LCMT1/PP2Ac-mediated autophagy inhibition.

Non-alcoholic fatty liver disease (NAFLD) is a progressive disorder of liver metabolism and has become the most common chronic liver disease worldwide. Benzo[a]pyrene (BaP) is recognized as a potent carcinogen, but the effect of low-dose BaP on the development of NAFLD has not been well-studied, and its molecular mechanism is still unknown. In this study, we demonstrated that low-dose BaP induced hepatic steatosis in a mouse model with a notable increase in hepatic lipid content. Interestingly, mRNA expression of genes related to fatty acids uptake or synthesis was not significantly altered after BaP exposure. Instead, we found that low-dose BaP promoted lipid deposition in primary mouse hepatocytes by inhibiting autophagy, which was regulated through Leucine carboxyl methyltransferase-1 (LCMT1) mediated Protein Phosphatases 2A subunit C (PP2Ac) methylation. The role of LCMT1 in BaP-induced steatosis was further validated in a liver-specific lcmt1 knockout (L-LCMT1 KO) mouse model. In this study, we provided evidence to support a novel mechanism by which BaP induces the development of hepatic steatosis through PP2Ac mediated autophagy inhibition. These findings provided new insight into the pathogenesis of NAFLD induced by environmental exposure to low-dose BaP.

Hepatic leucine carboxyl methyltransferase 1 (LCMT1) contributes to high fat diet-induced glucose intolerance through regulation of glycogen metabolism.

Impaired glucose regulation is one of the most important risk factors for type 2 diabetes mellitus (T2DM) and cardiovascular diseases, which have become a major public health issue worldwide. Dysregulation of carbohydrate metabolism in liver has been shown to play a critical role in the development of glucose intolerance but the molecular mechanism has not yet been fully understood. In this study, we investigated the role of hepatic LCMT1 in the regulation of glucose homeostasis using a liver-specific LCMT1 knockout mouse model. The hepatocyte-specific deletion of LCMT1 significantly upregulated the hepatic glycogen synthesis and glycogen accumulation in liver. We found that the liver-specific knockout of LCMT1 improved high fat diet-induced glucose intolerance and insulin resistance. Consistently, the high fat diet-induced downregulation of glucokinase (GCK) and other important glycogen synthesis genes were reversed in LCMT1 knockout liver. In addition, the expression of GCK was significantly upregulated in MIHA cells treated with siRNA targeting LCMT1 and improved glycogen synthesis. In this study, we provided evidences to support the role of hepatic LCMT1 in the development of glucose intolerance induced by high fat diet and demonstrated that inhibiting LCMT1 could be a novel therapeutic strategy for the treatment of glucose metabolism disorders.

LCMT1 indicates poor prognosis and is essential for cell proliferation in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most malignant type of cancers. Leuci carboxyl methyltransferase 1 (LCMT1) is a protein methyltransferase that plays an improtant regulatory role in both normal and cancer cells. The aim of this study is to evaluate the expression pattern and clinical significance of LCMT1 in HCC. METHODS: The expression pattern and clinical relevance of LCMT1 were determined using the Gene Expression Omnibus (GEO) database, the Cancer Genome Atlas (TCGA) program, and our datasets. Gain-of-function and loss-of-function studies were employed to investigate the cellular functions of LCMT1 in vitro and in vivo. Quantitative real-time polymerase chain reaction (RT-PCR) analysis, western blotting, enzymatic assay, and high-performance liquid chromatography were applied to reveal the underlying molecular functions of LCMT1. RESULTS: LCMT1 was upregulated in human HCC tissues, which correlated with a "poor" prognosis. The siRNA-mediated knockdown of LCMT1 inhibited glycolysis, promoted mitochondrial dysfunction, and increased intracellular pyruvate levels by upregulating the expression of alani-neglyoxylate and serine-pyruvate aminotransferase (AGXT). The overexpression of LCMT1 showed the opposite results. Silencing LCMT1 inhibited the proliferation of HCC cells in vitro and reduced the growth of tumor xenografts in mice. Mechanistically, the effect of LCMT1 on the proliferation of HCC cells was partially dependent on PP2A. CONCLUSIONS: Our data revealed a novel role of LCMT1 in the proliferation of HCC cells. In addition, we provided novel insights into the effects of glycolysis-related pathways on the LCMT1regulated progression of HCC, suggesting LCMT1 as a novel therapeutic target for HCC therapy.

Beliefs about medication and their association with adherence in Chinese patients with non-dialysis chronic kidney disease stages 3-5.

ABSTRACT: There is a scarcity of research into the impact of medication beliefs on adherence in patients with non-dialysis chronic kidney disease (CKD). This study is to determine the psychometric properties of the Chinese version of the Beliefs about Medicines Questionnaire (BMQ)-Specific among patients with non-dialysis CKD stages 3-5, and to assess the beliefs of CKD patients and their association with medication adherence.A cross-sectional study was conducted in CKD patients who recruited at the nephrology clinics of Xi'an Central Hospital, Xi'an, Shaanxi, China. The original BMQ-Specific was translated into Chinese. The internal consistency and test-retest reliability of the Chinese version of the BMQ-Specific scale were assessed, while exploratory and confirmatory factor analyses were also applied to determine its reliability and validity. The Kruskal-Wallis test and multiple ordered logistic regression were performed to identify the relationship between beliefs about and adherence to medication among CKD patients.This study recruited 248 patients. Cronbach's α values of the BMQ-Specific necessity and concern subscales were 0.826 and 0.820, respectively, with intraclass correlation coefficients of 0.784 and 0.732. Factor analysis showed that BMQ-Specific provided a good fit to the two-factor model. The adherence of patients was positively correlated with perceived necessity (r = 0.264, P < .001) and negatively correlated with concern (r = -0.294, P < .001). Medication adherence was significantly higher for the accepting group (high necessity and low concern scores) than for the ambivalent group (high necessity and concern scores; ß = -0.880, 95% confidence interval [CI] = -1.475 to -0.285), skeptical group (low necessity and high concern scores; ß = -2.620, 95% CI = -4.209 to -1.031) and indifferent group (low necessity and concern scores; ß = -0.918, 95% CI = -1.724 to -0.112).The Chinese version of BMQ-Specific exhibited satisfactory reliability and validity for use in patients with non-dialysis CKD stages 3-5 and has been demonstrated to be a reliable screening tool for clinicians to use to predict and identify the non-adherence behaviors of patients.