Association of TIMP1 Levels and Liver Disease Progression Among HIV/HCV Co-infected, HIV Mono-, HCV Mono-infected, and Healthy Groups from the MASH Cohort (FS09-07-19)

Abstract Objectives Antiretroviral therapy has increased life expectancy for HIV infected patients; however, this population is developing chronic illnesses associated with aging. Liver disease is a major cause of non-AIDS mortality, characterized by progressive fibrosis. Infection with HIV and with Hepatitis C Virus (HCV) promotes liver fibrogenesis. Tissue inhibitor of metalloproteinase-1 (TIMP1), inhibits fibrosis regression and is profibrogenic. Association between TIMP1 and liver disease progression in an aging population of HIV/HCV co-infected, HIV mono-infected, HCV mono-infected, and healthy groups from the Miami Adult Studies on HIV (MASH) cohort in Miami, Florida, was investigated. Methods Serum TIMP1 levels were determined by ELISA. A non-invasive estimate of liver fibrosis, FIB-4 score was calculated. Liver fibrosis was defined as FIB-4: Low <1.45, intermediate 1.45 < = FIB-4 < = 3.25, High >3.25. ANOVA with Tukey's test assessed the mean differences of FIB-4 score and TIMP1 level between groups, TIMP1 levels between 3 FIB-4 categories, and the effect of age on FIB-4 and TIMP1. Linear regression predicted the association of FIB-4 score and TIMP-1 level. Results Mean age of the cohort was 54.3 ± 8.1 years with no difference between groups. Mean FIB-4 for HIV/HCV co-infected group was the highest among the 4 groups (P < 0.05). Mean TIMP1 for HIV/HCV co-infected group was also the highest among the 4 groups (P < 0.05). FIB-4 and TIMP1 were associated and remained so (β = 0.01, SE = 0.002, P < 0.001) after adjusting for age. Mean TIMP1 for the high FIB-4 category was the highest among the 3 FIB-4 categories (P < 0.05). There was a direct effect of TIMP1 levels on FIB-4 category (P < 0.001). After adjusting for HIV/HCV co-infection (P < 0.001), HIV infection (P < 0.0001), HCV infection (P < 0.002), non-infection (P < 0.001) and age, the relationship between TIMP1 and FIB-4 remained significant. The adjusted TIMP1 mean for HIV/HCV co-infected group was significantly higher compared to HIV infected (P < 0.0001), HCV infected (P < 0.002), and healthy groups (P < 0.0001), regardless of age. Conclusions Age is a significant factor of liver diseases progression. Our findings of the highest levels of TIMP1 in HIV/HCV co-infected group, which had the highest liver fibrosis regardless of age, supports the role of TIMP1 as a regulator in the progression of hepatic fibrosis. Funding Sources National Institutes on Drug Abuse #5UO1DA040381.

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Loss of hepatic Flcn protects against fibrosis and inflammation by activating autophagy pathways

Scientific Reports ◽

10.1038/s41598-021-99958-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mathieu Paquette ◽

Ming Yan ◽

Josué M. J. Ramírez-Reyes ◽

Leeanna El-Houjeiri ◽

Marco Biondini ◽

...

Keyword(s):

Liver Disease ◽

Liver Fibrosis ◽

Fatty Liver ◽

Disease Progression ◽

Fatty Liver Disease ◽

Whole Body ◽

Alcoholic Fatty Liver ◽

Hepatocellular Damage ◽

Triglyceride Accumulation ◽

Liver Disease Progression

AbstractNon-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease worldwide and can progress to non-alcoholic steatohepatitis (NASH), which is characterized by triglyceride accumulation, inflammation, and fibrosis. No pharmacological agents are currently approved to treat these conditions, but it is clear now that modulation of lipid synthesis and autophagy are key biological mechanisms that could help reduce or prevent these liver diseases. The folliculin (FLCN) protein has been recently identified as a central regulatory node governing whole body energy homeostasis, and we hypothesized that FLCN regulates highly metabolic tissues like the liver. We thus generated a liver specific Flcn knockout mouse model to study its role in liver disease progression. Using the methionine- and choline-deficient diet to mimic liver fibrosis, we demonstrate that loss of Flcn reduced triglyceride accumulation, fibrosis, and inflammation in mice. In this aggressive liver disease setting, loss of Flcn led to activation of transcription factors TFEB and TFE3 to promote autophagy, promoting the degradation of intracellular lipid stores, ultimately resulting in reduced hepatocellular damage and inflammation. Hence, the activity of FLCN could be a promising target for small molecule drugs to treat liver fibrosis by specifically activating autophagy. Collectively, these results show an unexpected role for Flcn in fatty liver disease progression and highlight new potential treatment strategies.

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Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Cells ◽

10.3390/cells9040875 ◽

2020 ◽

Vol 9 (4) ◽

pp. 875 ◽

Cited By ~ 14

Author(s):

Natascha Roehlen ◽

Emilie Crouchet ◽

Thomas F. Baumert

Keyword(s):

Liver Disease ◽

Liver Fibrosis ◽

Disease Progression ◽

Liver Diseases ◽

Chronic Liver ◽

Specific Cell ◽

Chronic Liver Diseases ◽

Fibrotic Liver ◽

Liver Disease Progression ◽

Fibrotic Liver Disease

Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver injury and disease-specific cell responses, the progression of fibrotic liver disease follows shared patterns across the main liver disease etiologies. Scientific discoveries within the last decade have transformed the understanding of the mechanisms of liver fibrosis. Removal or elimination of the causative agent such as control or cure of viral infection has shown that liver fibrosis is reversible. However, reversal often occurs too slowly or too infrequent to avoid life-threatening complications particularly in advanced fibrosis. Thus, there is a huge unmet medical need for anti-fibrotic therapies to prevent liver disease progression and HCC development. However, while many anti-fibrotic candidate agents have shown robust effects in experimental animal models, their anti-fibrotic effects in clinical trials have been limited or absent. Thus, no approved therapy exists for liver fibrosis. In this review we summarize cellular drivers and molecular mechanisms of fibrogenesis in chronic liver diseases and discuss their impact for the development of urgently needed anti-fibrotic therapies.

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1894-P: HIF-2α Induced by Hypoxia Exacerbates Nonalcoholic Fatty Liver Disease Progression via Suppressing PPARα

Diabetes ◽

10.2337/db19-1894-p ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 1894-P

Author(s):

JIANDI CHEN ◽

JIANXU CHEN ◽

HUIRONG FU ◽

YUN LI ◽

SHUNKUI LUO ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Disease Progression ◽

Fatty Liver Disease ◽

Nonalcoholic Fatty Liver ◽

Liver Disease Progression

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Genetic variants of programmed cell death 1 are associated with HBV infection and liver disease progression

Scientific Reports ◽

10.1038/s41598-021-87537-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Nghiem Xuan Hoan ◽

Pham Thi Minh Huyen ◽

Mai Thanh Binh ◽

Ngo Tat Trung ◽

Dao Phuong Giang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Death ◽

Liver Disease ◽

Programmed Cell Death ◽

Disease Progression ◽

Infection Risk ◽

Hbv Infection ◽

Liver Disease Progression ◽

Increased Risk ◽

Programmed Cell Death 1

AbstractThe inhibitory effects of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) modulates T-cell depletion. T-cell depletion is one of the key mechanisms of hepatitis B virus (HBV) persistence, in particular liver disease progression and the development of hepatocellular carcinoma (HCC). This case–control study aimed to understand the significance of PD-1 polymorphisms (PD-1.5 and PD-1.9) association with HBV infection risk and HBV-induced liver disease progression. Genotyping of PD-1.5 and PD-1.9 variants was performed by direct Sanger sequencing in 682 HBV-infected patients including chronic hepatitis (CHB, n = 193), liver cirrhosis (LC, n = 183), hepatocellular carcinoma (HCC, n = 306) and 283 healthy controls (HC). To analyze the association of PD-1 variants with liver disease progression, a binary logistic regression, adjusted for age and gender, was performed using different genetic models. The PD-1.9 T allele and PD-1.9 TT genotype are significantly associated with increased risk of LC, HCC, and LC + HCC. The frequencies of PD-1.5 TT genotype and PD-1.5 T allele are significantly higher in HCC compared to LC patients. The haplotype CT (PD-1.5 C and PD-1.9 T) was significantly associated with increased risk of LC, HCC, and LC + HCC. In addition, the TC (PD-1.5 T and PD-1.9 C) haplotype was associated with the risk of HCC compared to non-HCC. The PD-1.5 CC, PD-1.9 TT, genotype, and the CC (PD-1.5 C and PD-1.9) haplotype are associated with unfavorable laboratory parameters in chronic hepatitis B patients. PD-1.5 and PD1.9 are useful prognostic predictors for HBV infection risk and liver disease progression.

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Impact of genotype 3 on clinical outcome in patients with hepatitis C: both diabetes meliitus and liver disease progression

Journal of Hepatology ◽

10.1016/s0168-8278(17)31905-0 ◽

2017 ◽

Vol 66 (1) ◽

pp. S711-S712

Author(s):

W. Zanjir ◽

R. Maan ◽

B. Hansen ◽

O. Cerocchi ◽

H. Janssen ◽

...

Keyword(s):

Liver Disease ◽

Hepatitis C ◽

Clinical Outcome ◽

Disease Progression ◽

Genotype 3 ◽

Liver Disease Progression

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Dynamin-related protein 1 deficiency accelerates lipopolysaccharide-induced acute liver injury and inflammation in mice

Communications Biology ◽

10.1038/s42003-021-02413-6 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Lixiang Wang ◽

Xin Li ◽

Yuki Hanada ◽

Nao Hasuzawa ◽

Yoshinori Moriyama ◽

...

Keyword(s):

Liver Disease ◽

Liver Injury ◽

Er Stress ◽

Disease Progression ◽

Acute Liver Injury ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Mitochondrial Fusion ◽

Related Protein ◽

Liver Disease Progression

AbstractMitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics. Mitochondrial fusion defects in the liver cause a non-alcoholic steatohepatitis-like phenotype and liver cancer. However, whether mitochondrial fission defect directly impair liver function and stimulate liver disease progression, too, is unclear. Dynamin-related protein 1 (DRP1) is a key factor controlling mitochondrial fission. We hypothesized that DRP1 defects are a causal factor directly involved in liver disease development and stimulate liver disease progression. Drp1 defects directly promoted endoplasmic reticulum (ER) stress, hepatocyte death, and subsequently induced infiltration of inflammatory macrophages. Drp1 deletion increased the expression of numerous genes involved in the immune response and DNA damage in Drp1LiKO mouse primary hepatocytes. We administered lipopolysaccharide (LPS) to liver-specific Drp1-knockout (Drp1LiKO) mice and observed an increased inflammatory cytokine expression in the liver and serum caused by exaggerated ER stress and enhanced inflammasome activation. This study indicates that Drp1 defect-induced mitochondrial dynamics dysfunction directly regulates the fate and function of hepatocytes and enhances LPS-induced acute liver injury in vivo.

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