A dipeptidyl peptidase-IV inhibitor improves hepatic steatosis and insulin resistance by AMPK-dependent and JNK-dependent inhibition of LECT2 expression

Hwang, Hwan-Jin; Jung, Tae Woo; Kim, Baek-hui; Hong, Ho Cheol; Seo, Ji A; Kim, Sin Gon; Kim, Nan Hee; Choi, Kyung Mook; Choi, Dong Seop; Baik, Sei Hyun; Yoo, Hye Jin

doi:10.1016/j.bcp.2015.08.098

Cited by 69 publications

(68 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Phosphorylation of Akt can stimulate mTOR by phosphorylating it at Ser2448. Multiple evidences have suggested that dysregulation of the Akt/mTOR signaling pathway is the major molecular mechanism underlying the metabolic dysfunctions such as NAFLD [26]. In the present study, we showed that hepatic ClC-2 deficiency in HFD mice enhanced phosphorylation of IRS-1 at Tyr608 as well as further inhibited Ser307 phosphorylation induced by acute intraperitoneal injection of insulin.…”

Section: Discussionsupporting

confidence: 62%

Lack of ClC-2 Alleviates High Fat Diet-Induced Insulin Resistance and Non-Alcoholic Fatty Liver Disease

Fu¹,

Cui

Zhang³

2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. This study aims to investigate whether chloride channel 2 (ClC-2) is involved in high fat diet (HFD)-induced NAFLD and possible molecular mechanisms. Methods: ClC-2 expression was liver-specifically downregulated using adeno-associated virus in C57BL/6 mice treated with a chow diet or HFD for 12 weeks. Peripheral blood and liver tissues were collected for biochemical and pathological estimation respectively. Western blotting was applied to detect the protein expressions of lipid synthesis-related enzymes and the phosphorylated level of IRS-1, Akt and mTOR. Results: ClC-2 mRNA level was significantly increased in patients with non-alcoholic steatohepatitis, which positively correlated with the plasma levels of alanine transaminase (ALT), aspartate transaminase (AST) and insulin. Knockdown of ClC-2 in liver attenuated HFD-induced weight gain, obesity, hepatocellular ballooning, and liver lipid accumulation and fibrosis, accompanied by reduced plasma free fatty acid (FFA), triglyceride (TG), total cholesterol (TC), ALT, AST, glucose and insulin levels and homeostasis model of insulin resistance (HOMA-IR) value. Moreover, HFD-treated mice lacking ClC-2 showed inhibited hepatic lipid accumulation via regulating lipid metabolism through decreasing sterol regulatory element binding protein (SREBP)-1c expression and its downstream targeting enzymes such as fatty acid synthase (FAS), HMG-CoA reductase (HMGCR) and acetyl-Coenzyme A carboxylase (ACCα). In addition, in vivo and in vitro results demonstrated that ClC-2 downregulation in HFD-treated mice or HepG2 cells increased the sensitivity to insulin via activation of IRS-1/Akt/mTOR signaling pathway. Conclusion: Our present study reveals a critical role of ClC-2 in regulating metabolic diseases. Mice lacking ClC-2 are associated with a remarkably beneficial metabolic phenotype, suggesting that decreasing ClC-2 may be an attractive therapeutic strategy for the treatment of NAFLD.

show abstract

Section: Discussionsupporting

confidence: 62%

Lack of ClC-2 Alleviates High Fat Diet-Induced Insulin Resistance and Non-Alcoholic Fatty Liver Disease

Fu¹,

Cui

Zhang³

2018

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…Previously, we demonstrated that LECT2 increased mammalian target of rapamycin (mTOR) phosphorylation, sterol regulatory element-binding protein (SREBP)-1 cleavage, lipid accumulation, and insulin resistance in HepG2 cells [11]. Furthermore, in our previous research, LECT2 treatment efficiently increased the expression of adhesion molecules and pro-inflammatory cytokines in HUVECs and THP-1 cells [12], suggesting the possibility that LECT2 might directly mediate atherosclerotic inflammatory reactions in human endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…They also showed that the expression of the genes involved in mitochondria and myogenesis was up-regulated in the muscle of LECT -/- mice [10], emphasizing the pivotal role of LECT2 on the provocation of peripheral insulin resistance. Recently, we reported that a dipeptidyl peptidase 4 inhibitor improves hepatic steatosis as well as insulin resistance through AMP-activated protein kinase (AMPK)- and JNK-dependent inhibition of LECT2 expression [11]. Furthermore, we found that LECT2 induces pro-inflammatory cytokines and adhesion molecules via CD209 receptor-mediated JNK phosphorylation in human umbilical vein endothelial cells (HUVECs) [12].…”

Section: Introductionmentioning

confidence: 99%

Association of leukocyte cell-derived chemotaxin 2 (LECT2) with NAFLD, metabolic syndrome, and atherosclerosis

et al. 2017

Self Cite

View full text Add to dashboard Cite

ObjectivePrevious studies have shown that leukocyte cell-derived chemotaxin 2 (LECT2), a recently discovered hepatokine, is associated with the inflammatory response and insulin resistance. We examined circulating plasma LECT2 levels in the subjects with non-alcoholic fatty liver disease (NAFLD) or metabolic syndrome.MethodsWe analyzed plasma LECT2 levels from the subjects of age- and sex-matched 320 adults with or without NAFLD who completed a health check-up at the Health Promotion Center of Korea University Guro Hospital.ResultsIndividuals with NAFLD showed significantly higher LECT2 levels (31.2 [20.9, 41.5] vs. 24.5[16.3, 32.7] ng/ml, P <0.001) as well as components of MetS compared to those without NAFLD. Furthermore, circulating LECT2 concentrations were greater in subjects with MetS (32.6 [17.8, 45.0] vs. 27.0 [18.7, 33.7] ng/ml, P = 0.016) and were associated with anthropometric measures of obesity, lipid profiles, high sensitivity C-reactive protein (hsCRP) and liver aminotransferase levels. However, there was no significant relationship between LECT2 levels and indicators of subclinical atherosclerosis, such as carotid intima-media thickness (CIMT) and brachial ankle pulse wave velocity (baPWV). Multivariate analysis demonstrated a progressively increasing trend of odds ratios for NAFLD according to quartiles of LECT2 levels after adjusting for risk factors, although the relationship was attenuated after further adjustment for waist circumference and lipid levels.ConclusionCirculating LECT2 concentrations were increased in individuals with NAFLD and those with MetS, but not in those with atherosclerosis. The relationship between LECT2 and both NAFLD and MetS might be mediated by its association with abdominal obesity and lipid metabolism.Trial registrationClinicaltrials.gov NCT01594710

show abstract

“…In addition to our findings, there are several literatures reporting the relationship between DPP4 and steatosis. Gemigliptin, an inhibitor of DPP4, improved hepatic steatosis and insulin resistance in HF diet-fed mice, by AMP-activated protein kinase-dependent and c-Jun N-terminal kinase-dependent mechanisms [44]. In addition, DPP-4 inhibition could ameliorate hepatic steatosis and insulin resistance by suppressing hepatic TG and diacylglycerol accumulation through enhanced mitochondrial carbohydrate utilization and hepatic TG secretion/export with a concomitant reduction of uric acid production [45].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of hepatocyte nuclear factor 1b induces hepatic steatosis through DPP4/NOX1-mediated regulation of superoxide

Long

Cao

et al. 2017

Free Radical Biology and Medicine

View full text Add to dashboard Cite

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder that is closely associated with insulin resistance and type 2 diabetes. Previous studies have suggested that hepatocyte nuclear factor 1b (HNF1b) ameliorates insulin resistance. However, the role of HNF1b in the regulation of lipid metabolism and hepatic steatosis remains poorly understood. We found that HNF1b expression was decreased in steatotic livers. We injected mice with lentivirus (LV) expressing HNF1b shRNA to generate mice with hepatic knockdown of HNF1b. We also injected high fat (HF) diet-induced obese and db/db diabetic mice with LV expressing HNF1b to overexpress HNF1b. Knockdown of HNF1b increased hepatic lipid contents and induced insulin resistance in mice and in hepatocytes. Knockdown of HNF1b worsened HF diet-induced increases in hepatic lipid contents, liver injury and insulin resistance in mice and PA-induced lipid accumulation and impaired insulin signaling in hepatocytes. Moreover, overexpression of HNF1b alleviated HF diet-induced increases in hepatic lipid content and insulin resistance in mice. Knockdown of HNF1b increased expression of genes associated with lipogenensis and endoplasmic reticulum (ER) stress. DPP4 and NOX1 expression was increased by knockdown of HNF1b and HNF1b directly bound with the promoters of DPP4 and NOX1. Overexpression of DPP4 or NOX1 was associated with an increase in lipid droplets in hepatocytes and decreased expression of DPP4 or NOX1 suppressed the effects of knockdown of HNF1b knockdown on triglyceride (TG) formation and insulin signaling. Knockdown of HNF1b increased superoxide level and decreased glutathione content, which was inhibited by downregulation of DPP4 and NOX1. N-acetylcysteine (NAC) suppressed HNF1b knockdown-induced ER stress, TG formation and insulin resistance. Palmitic acid (PA) decreased HNF1b expression which was inhibited by NAC. Taken together, these studies demonstrate that HNF1b plays an essential role in controlling hepatic TG homeostasis and insulin sensitivity by regulating DPP4/NOX1mediated generation of superoxide.

show abstract

A dipeptidyl peptidase-IV inhibitor improves hepatic steatosis and insulin resistance by AMPK-dependent and JNK-dependent inhibition of LECT2 expression

Cited by 69 publications

References 32 publications

Lack of ClC-2 Alleviates High Fat Diet-Induced Insulin Resistance and Non-Alcoholic Fatty Liver Disease

Lack of ClC-2 Alleviates High Fat Diet-Induced Insulin Resistance and Non-Alcoholic Fatty Liver Disease

Association of leukocyte cell-derived chemotaxin 2 (LECT2) with NAFLD, metabolic syndrome, and atherosclerosis

Inhibition of hepatocyte nuclear factor 1b induces hepatic steatosis through DPP4/NOX1-mediated regulation of superoxide

Contact Info

Product

Resources

About