Verification of B-lymphocyte activating factor’s involvement in the exacerbation of insulin resistance as well as an autoimmune response in patients with nonalcoholic steatohepatitis and patients with HCV-related chronic liver disease

Abstract Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and can lead to multiple complications, including non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. The fibrotic liver is characterized by the pathological accumulation of extracellular matrix (ECM) proteins. Type VI collagen alpha3 (Col6a3) is a biomarker of hepatic fibrosis, and its cleaved form, endotrophin (ETP), plays a critical role in adipose tissue dysfunction, insulin resistance, and breast cancer development. Here, we studied the effects of the Col6a3-derived peptide ETP on the progression of chronic liver diseases, such as NASH and liver cancer. We used a doxycycline (Dox)-inducible liver-specific ETP-overexpressing mouse model on a NAFLD-prone (liver-specific SREBP1a transgenic) background. For this, we evaluated the consequences of local ETP expression in the liver and its effect on hepatic inflammation, fibrosis, and insulin resistance. Accumulation of ETP in the liver induced hepatic inflammation and the development of fibrosis with associated insulin resistance. Surprisingly, ETP overexpression also led to the emergence of liver cancer within 10 months in the SREBP1a transgenic background. Our data revealed that ETP can act as a “second hit” during the progression of NAFLD and can play an important role in the development of NASH and hepatocellular carcinoma (HCC). These observations firmly link elevated levels of ETP to chronic liver disease.

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Insulin resistance and plasma glucose tolerance abnormalities in Nigerians with chronic liver disease

Diabetes & Metabolic Syndrome Clinical Research & Reviews ◽

10.1016/j.dsx.2019.05.014 ◽

2019 ◽

Vol 13 (3) ◽

pp. 2208-2213

Author(s):

Oluwadamilola O. Amjo ◽

David O. Soyoye ◽

Ifeoluwa Amjo ◽

Olaoluwatomi T. Yusuff ◽

Babatope A. Kolawole ◽

...

Keyword(s):

Insulin Resistance ◽

Liver Disease ◽

Glucose Tolerance ◽

Chronic Liver Disease ◽

Plasma Glucose ◽

Chronic Liver

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Insulin resistance and chronic liver disease

World Journal of Hepatology ◽

10.4254/wjh.v3.i5.99 ◽

2011 ◽

Vol 3 (5) ◽

pp. 99 ◽

Cited By ~ 49

Author(s):

Takumi Kawaguchi

Keyword(s):

Insulin Resistance ◽

Liver Disease ◽

Chronic Liver Disease ◽

Chronic Liver

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Exacerbation of Insulin Resistance and Hepatic Steatosis Deriving from Zinc Deficiency in Patients with HCV-Related Chronic Liver Disease

Biological Trace Element Research ◽

10.1007/s12011-014-0177-3 ◽

2014 ◽

Vol 163 (1-2) ◽

pp. 81-88 ◽

Cited By ~ 22

Author(s):

Takashi Himoto ◽

Takako Nomura ◽

Joji Tani ◽

Hisaaki Miyoshi ◽

Asahiro Morishita ◽

...

Keyword(s):

Insulin Resistance ◽

Liver Disease ◽

Chronic Liver Disease ◽

Hepatic Steatosis ◽

Zinc Deficiency ◽

Chronic Liver

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Insulin Resistance and Hyperinsulinemia in Patients with Chronic Liver Disease and Hepatocellular Carcinoma

Clinical medicine Endocrinology and diabetes ◽

10.4137/cmed.s3116 ◽

2009 ◽

Vol 2 ◽

pp. CMED.S3116 ◽

Cited By ~ 1

Author(s):

Valter Donadon ◽

Massimiliano Balbi ◽

Antonio Perciaccante ◽

Pietro Casarin ◽

Giorgio Zanette

Keyword(s):

Hepatocellular Carcinoma ◽

Insulin Resistance ◽

Liver Disease ◽

Chronic Liver Disease ◽

Healthy Subjects ◽

Chronic Liver ◽

Metabolic Factors ◽

Mean Values ◽

The Mean

Objectives To investigate the role of insulin resistance (IR) and insulin plasma levels (IRI) in patients with chronic liver disease (CLD) and hepatocellular carcinoma (HCC). Methods We recruited the following patients: 125 with HCC, 128 with liver cirrhosis (LC) and 133 with chronic hepatitis C (CHC). IR was assessed by the HOMA-IR method. To define IR and hyperinsulinemia we selected as a cut-off level, the value of the 80th percentile for HOMA-IR (2.72) and IRI (11.18) in 113 healthy subjects. Results The mean levels of HOMA-IR and IRI increase progressively among CHC (2.7 ± 2.9 and 11.5 ± 10.5, respectively), LC (5.4 ± 4.5 and 17.6 ± 11.2) and HCC (6.4 ± 9.8 and 18.2 ± 18.8). In the upper quintiles for HOMA-IR and IRI, the frequency of patients in the LC and HCC groups was twice as much in CHC cases. HCC with DM2 have the greatest percentage above the 80th percentile of HOMA-IR, their quintiles distribution is inverted and HOMA-IR mean values are significantly higher in comparison with HCC without DM2 cases. Discussion Our study shows that the association between IR and CLD begins in the early stages of liver fibrosis. DM2 increases HOMA-IR and IRI mean levels in HCC patients and these metabolic factors could play a major role in the link between diabetes mellitus and hepatocarcinoma.

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Altered Metabolic Profile and Adipocyte Insulin Resistance Mark Severe Liver Fibrosis in Patients with Chronic Liver Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20246333 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6333 ◽

Cited By ~ 3

Author(s):

Melania Gaggini ◽

Fabrizia Carli ◽

Chiara Rosso ◽

Ramy Younes ◽

Romina D’Aurizio ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Liver Disease ◽

Amino Acid ◽

Liver Fibrosis ◽

Chronic Liver Disease ◽

Chronic Liver ◽

Hcv Infection ◽

Severe Liver ◽

Novel Biomarkers

Metabolomics/lipidomics are important tools to identify novel biomarkers associated with liver damage. Patients with chronic liver disease (CLD) and hepatitis C virus (HCV) infection often have alterations in glucose, lipid and protein metabolism. The aim of this study was to evaluate if dysfunctional lipid and amino acid metabolism was associated with fibrosis severity and insulin resistance in CLD/HCV patients. We analyzed the baseline sera of 75 subjects with CLD/HCV infection HCV genotype-1, with proven liver biopsy prior to antiviral treatment. We measured amino acid (AA) and lipid concentration by gas and liquid chromatography-mass spectrometry respectively. Alterations in peripheral glucose metabolism due to insulin resistance (IR) were assesed by HOMA-IR (Glucose x Insulin/22.5), while adipose tissue IR was estimated as (Adipo-IR = Free Fatty Acids x Insulin). Baseline HOMA-IR and Adipo-IR were related to the degree of liver fibrosis. Reduction in ceramides 18:1/22:0, 18:1/24:0, diacylglycerol 42:6 and increased phosphocholine 40:6 were associated with higher fibrosis. Adipo-IR was related to lower levels of lysophosphatidylcholine 14:0 and 18:2 and with higher levels of sphingomyelin 18:2/24:0 and 18:2/24:1. Almost all AA were positively associated with Adipo-IR but not with HOMA-IR. We further confirmed the potential use of metabolomics and lipidomics in CLD/HCV subjects finding novel biomarkers of hepatic fibrosis and show that the adipose tissue IR is associated with more severe liver disease and is an important marker not only of altered lipid but also AA metabolism.

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Article Commentary: Clinical Medicine: Endocrinology and Diabetes: Insulin Resistance–-a Link between Inflammation and Hepatocarcinogenesis?

Clinical medicine Endocrinology and diabetes ◽

10.4137/cmed.s3497 ◽

2009 ◽

Vol 2 ◽

pp. CMED.S3497

Author(s):

Jörn M. Schattenberg

Keyword(s):

Risk Factors ◽

Insulin Resistance ◽

Liver Disease ◽

Signaling Pathways ◽

Chronic Liver Disease ◽

Liver Cell ◽

Cell Injury ◽

Chronic Liver ◽

Obesity And Diabetes ◽

Liver Cell Injury

The incidence of hepatocellular carcinoma (HCC) is increasing world wide. The risk factors for the development of HCC include liver cirrhosis, chronic alcohol intake, and chronic viral hepatitis. These conditions are associated with inflammation, liver cell injury, and oxidative stress. The signaling pathways that contribute to liver cell injury have been shown to also promote insulin resistance in hepatocytes. On the other hand, obesity and diabetes have been suggested as risk factors for the development of chronic liver disease and HCC. The molecular mediators (e.g. stress kinases) and signaling pathways that contribute to cellular injury, proliferation and insulin resistance are also activated in chronic liver disease. At this time it is still unknown whether (1) IR will help to identify patients that are of increased risk for progressive liver disease or (2) if improving IR will be beneficial to patients with chronic liver disease. Future research will have to expand our knowledge on mediators of inflammation and liver cell injury within clinical trials to establish whether IR should be included in every hepatologists work up as a cofactor for chronic liver disease.

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