About

Mario Chojkier is a Professor In Residence in the Department of Medicine at UC San Diego. His educational background includes an MD from Buenos Aires University, where he graduated Magna Cum Laude in 1970, and postgraduate training comprising a fellowship at Yale University in 1979, as well as residency programs at Yale University and Instituto Nacional de la Salud in Argentina. His research focuses on molecular mechanisms of liver inflammation and injury, fibrosis, and hepatocyte proliferation, with a particular emphasis on therapeutic development for lung and liver fibrosis. He has been involved in numerous research projects, including studies on C/EBP-beta phosphorylation and peptides for the treatment of hepatic and lung injuries, supported by various NIH and Department of Defense grants. His work contributes to understanding and developing treatments for fibrotic diseases, with a significant record of leadership in clinical trials and translational research.

Research topics

• Medicine
• Internal medicine
• Biology
• Chemistry
• Molecular biology

Selected publications

• Determination of Collagen Synthesis in Tissue and Cell Culture Systems

  2018-01-18 · 44 citations

  book-chapter

  This chapter covers all aspects of experiments designed to measure the rate of collagen synthesis in whole animals, isolated tissues, or cell cultures. It describes methods to determine the relative and absolute rates of collagen synthesis and the rate of degradation. The disadvantage of biochemical method is that two reactions are measured: collagen synthesis and proline hydroxylation. Many commercial preparations of purified collagenase have been found to contain a substantial amount of noncollagen proteolytic enzyme activity. In many cell cultures, however, procollagen is processed quite slowly, so that various intermediates and very little mature a-chains are present, especially in short-term labeling experiments. In order to determine the absolute rate of synthesis of a protein in molar terms, the specific activity of the radioactive amino acid in the precursor amino acid pool of the cell or tissue must be measured.

  PublisherDOI

• Blood Microbiome Quantity and the Hyperdynamic Circulation in Decompensated Cirrhotic Patients

  PLoS ONE · 2017-02-01 · 59 citations

  articleOpen access

  BACKGROUND: Recently, a complex microbiome was comprehensibly characterized in the serum and ascitic fluid of cirrhotic patients. In the current study, we investigated for the first time the induction of inflammatory pathways and Nitric Oxide, as well as the systemic hemodynamics in conjunction with the blood microbiome in a Child-Pugh class B cirrhotic cohort. METHODS AND FINDINGS: We used the Intestinal Infections Microbial DNA qPCR Array to screen for 53 bacterial DNA from the gut in the blood. Assays were designed using the 16S rRNA gene as a target, and PCR amplification primers (based on the Human Microbiome Project) and hydrolysis-probe detection. Eighteen systemic hemodynamic parameters were measured non-invasively by impedance cardiography using the BioZ ICG monitor. The inflammatory response was assessed by measuring blood cytokines, Nitric Oxide RNA arrays, and Nitric Oxide. In the blood of this cirrhotic cohort, we detected 19 of 53 bacterial species tested. The number of bacterial species was markedly increased in the blood of cirrhotic patients compared to control individuals (0.2+/-0.4 vs 3.1+/-2.3; 95% CI: 1.3 to 4.9; P = 0.0030). The total bacterial DNA was also increased in the blood of cirrhotic subjects compared to control subjects (0.2+/- 1.1 vs 41.8+/-132.1; 95% CI: 6.0 to 77.2; P = 0.0022). In the cirrhotic cohort, the Cardiac Output increased by 37% and the Systemic Vascular Resistance decreased by 40% (P< 0.00001 for both compared to control subjects). Systemic Vascular Resistance was inversely correlated to blood bacterial DNA quantity (- 0.621; 95% CI -0.843 to -0.218; P = 0.0060), blood bacterial species number (- 0.593; 95% CI -0.83 to -0.175; P = 0.0095; logistic regression: Chi Square = 5.8877; P = 0.0152), and serum Nitric Oxide (- 0.705; 95% CI -0.881 to -0.355; P = 0.0011). Many members of the Nitric Oxide signaling pathway gene family were increased in cirrhotic subjects. CONCLUSIONS: Our study identified blood bacterial DNA in ~ 90% of the cirrhotic patients without clinical evidences of infection, and suggests that the quantity of bacterial DNA in blood may stimulate signaling pathways, including Nitric Oxide, that could decrease systemic vascular resistance and increase cardiac output.

  PublisherOA PDFDOI

• Hepatitis C Virus Infection in Patients is Associated With C/EBPβ-Thr266 Phosphorylation and Hepatocyte Proliferation

  Journal of Gastroenterology and Hepatology Research · 2016-01-01

  articleOpen access

  AIM: Hepatitis C virus (HCV) infection in patients induces hepatocyte proliferation and also hepatocellular carcinoma. The mechanisms and the liver acinar distribution of the HCV infection remain unclear. The aim of this study was to determine the liver acinar localization of the infectious HCV and whether HCV infection is associated with the expression of proteins known to modulate hepatocyte proliferation. METHODS: We analyzed normal (n = 6), HCV genotype 1-infected non cirrhotic (n = 6) and HCV genotype 1-infected cirrhotic liver samples (n = 6). We performed immunofluorescent studies using antibodies against HCV Core, Glutamine synthetase (as a marker of hepatic acinar zone-3 in normal livers); phosphorylated C/EBPβ-Thr266 (since it is required for Transforming Growth Factorα-and Hepatic Growth Factor - induced hepatocyte proliferation) and ki-67 (as an indicator of hepatocyte proliferation). Also, we analyzed by QRT-PCR a proliferation microarray to compare the expression of genes associated with cell proliferation in HCV-infected patients. RESULTS: In patients with HCV infection, the HCV Core protein was preferentiallyco-localized with hepatocytes expressing Glutamine synthetase, phosphorylated C/EBPβ-Thr266, HIF-1α and β-Catenin. As expected, phosphorylated C/EBPβ-Thr266 was associated with hepatocyte proliferation in these patients. HCV infection markedly increased hepatocyte proliferation. CONCLUSION: This study demonstrates that HCV infection is preferentially localized to an expanded acinar zone expressing GS, where enhanced hepatocyte proliferation occurs in association with phosphorylated C/EBPβ-Thr266. A better understanding of the mechanisms of HCV infection may facilitate additional studies and potential therapeutic interventions.

  PublisherOA PDFDOI

• C/EBPβ-Thr217 Phosphorylation Stimulates Macrophage Inflammasome Activation and Liver Injury

  Scientific Reports · 2016-04-12 · 5 citations

  articleOpen accessSenior author

  Amplification of liver injury is mediated by macrophages but the signaling by which the macrophage inflammasome enhances liver injury is not completely understood. The CCAAT/Enhancer Binding Protein-β (C/EBPβ) is a critical signaling molecule for macrophages because expression of a dominant inhibitor of C/EBPβ DNA-binding sites or a targeted deletion of C/EBPβ results in impaired macrophage differentiation. We reported that expression of the phosphorylation-mutant C/EBPβ-Glu217, which mimics phosphorylated C/EBPβ-Thr217, was sufficient to confer macrophage survival to Anthrax lethal toxin. Here, using primary hepatocytes, primary liver macrophages, dominant positive and negative transgenic mice of the C/EBPβ-Thr217 phosphoacceptor, macrophage ablation, and an inhibitory peptide of C/EBPβ-Thr217 phosphorylation, we determined that this phosphorylation is essential for the activation of the inflammasome in liver macrophages and for the hepatocyte apoptosis induced by hepatotoxins that results in liver injury. Similar findings were observed in the livers of patients with acute injury induced by Toxic Oil Syndrome.

  PublisherOA PDFDOI

• The RSK-inhibitory peptide blocks hepatic stellate cell activation and liver fibrosis induced by CCl&lt;sub&gt;4&lt;/sub&gt;.

  Figshare · 2015-12-02

  paratextOpen accessSenior author

  &lt;p&gt;A Caspase 8 activity was measured in lysates from HSC isolated from C/EBPβ&lt;sup&gt;+/+ &lt;/sup&gt;[wt] and C/EBPβ-Ala217 mice untreated or treated with CCl&lt;sub&gt;4&lt;/sub&gt; for 24 hr. Caspase activity was increased in C/EBPβ-Ala217 mice treated with CCl&lt;sub&gt;4&lt;/sub&gt;. Results from triplicate samples of two independent experiments are shown. B. Caspase activation in a cell-free system was determined as described in &lt;a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001372#s4" target="_blank"&gt;Methods&lt;/a&gt;. The Ac-KAla217VD-CHO peptide enhanced the activation of caspase 8 at picomolar concentrations. Baseline caspase 8 activity was 3.8 U (100%). Results from triplicate samples of three independent experiments are shown (&lt;i&gt;P&lt;0.01&lt;/i&gt; for the Ac-KAla217VD-CHO peptide). C. Animals received a single injection of CCl&lt;sub&gt;4 &lt;/sub&gt;or mineral oil as described in &lt;a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001372#s4" target="_blank"&gt;Methods&lt;/a&gt;. α-SMA (red) and C/EBPβ-PhosphoThr217 (green) were identified as described in &lt;a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001372#s4" target="_blank"&gt;Materials and methods&lt;/a&gt;. Treatment with the cell permeant Ac-KAla217VD-CHO peptide blocked the expression of α-SMA and C/EBPβ-PhosphoThr217. D. PCNA (red) and active caspase 3 (green) were identified as described in &lt;a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001372#s4" target="_blank"&gt;Materials and methods&lt;/a&gt;. Treatment with the Ac-KAla217VD–CHO peptide blocked the expression of PCNA and induced active caspase 3. E. C/EBPβ&lt;sup&gt;+/+&lt;/sup&gt; (wt) mice with severe liver fibrosis after treatment with CCl&lt;sub&gt;4&lt;/sub&gt; for 8 weeks, while continuing on CCl&lt;sub&gt;4&lt;/sub&gt;, received the RSK inhibitory peptide (5 µg IP, three times/week, for week 9 followed by 1 µg IP, three times/week for weeks 10–12 or 10–16). These are representative Mallory's trichrome stain for liver fibrosis (in blue). All control mice (&lt;i&gt;n&lt;/i&gt;: 8 at 8-weeks; &lt;i&gt;n&lt;/i&gt;: 8 at 12-weeks; and &lt;i&gt;n&lt;/i&gt;: 8 at 16-weeks) developed severe liver fibrosis, while mice receiving the RSK-inbitory peptide (&lt;i&gt;n&lt;/i&gt;: 8 at 12-weeks; and &lt;i&gt;n&lt;/i&gt;: 8 at 16-weeks) had no fibrosis or only minimal liver fibrosis (&lt;i&gt;P&lt;0.01&lt;/i&gt;). F. Analysis of hepatic collagen content by the Sirius red collagen–binding assay showed a ∼2.5 to 3-fold increase in C/EBPβ&lt;sup&gt;+/+&lt;/sup&gt; mice treated with CCl&lt;sub&gt;4&lt;/sub&gt; (&lt;i&gt;n&lt;/i&gt;: 8 for 8 weeks; &lt;i&gt;n&lt;/i&gt;: 8 for 12 weeks and &lt;i&gt;n&lt;/i&gt;: 8 for the 16 weeks), compared to animals also receiving the RSK-inbitory peptide (&lt;i&gt;n&lt;/i&gt;: 6 for 12weeks; &lt;i&gt;n&lt;/i&gt;: 8 for 16 weeks; &lt;i&gt;P&lt;0.01&lt;/i&gt;). G. Analysis of hepatic collagen content by the hydroxyproline assay, showed a 2.2-, 3.5- and 5.3-fold increase in C/EBPβ&lt;sup&gt;+/+&lt;/sup&gt; mice treated with CCl&lt;sub&gt;4&lt;/sub&gt;, respectively (&lt;i&gt;n&lt;/i&gt;: 8 for 8 weeks; &lt;i&gt;n&lt;/i&gt;: 7 for 12 weeks and &lt;i&gt;n&lt;/i&gt;: 7 for the 16 weeks), compared to animals also receiving the RSK-inbitory peptide (&lt;i&gt;n&lt;/i&gt;: 6 for 12weeks; &lt;i&gt;n&lt;/i&gt;: 8 for 16 weeks; &lt;i&gt;P&lt;0.01&lt;/i&gt;).&lt;/p&gt;

  PublisherDOI

• Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection

  New England Journal of Medicine · 2014-04-12 · 1706 citations

  articleOpen access

  BACKGROUND: In phase 2 studies, treatment with the all-oral combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir resulted in high rates of sustained virologic response among previously untreated patients with hepatitis C virus (HCV) genotype 1 infection. METHODS: We conducted a phase 3, open-label study involving previously untreated patients with chronic HCV genotype 1 infection. Patients were randomly assigned in a 1:1:1:1 ratio to receive ledipasvir and sofosbuvir in a fixed-dose combination tablet once daily for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis, 12% were black, and 67% had HCV genotype 1a infection. The rates of sustained virologic response were 99% (95% confidence interval [CI], 96 to 100) in the group that received 12 weeks of ledipasvir-sofosbuvir; 97% (95% CI, 94 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir plus ribavirin; 98% (95% CI, 95 to 99) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 97 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir plus ribavirin. No patient in either 12-week group discontinued ledipasvir-sofosbuvir owing to an adverse event. The most common adverse events were fatigue, headache, insomnia, and nausea. CONCLUSIONS: Once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection. (Funded by Gilead Sciences; ION-1 ClinicalTrials.gov number NCT01701401.).

  PublisherOA PDFDOI

• No Significant Effects of Ethyl-Eicosapentanoic Acid on Histologic Features of Nonalcoholic Steatohepatitis in a Phase 2 Trial

  Gastroenterology · 2014-05-09 · 307 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Ledipasvir and Sofosbuvir for 8 or 12 Weeks for Chronic HCV without Cirrhosis

  New England Journal of Medicine · 2014-04-11 · 1125 citations

  articleOpen access

  BACKGROUND: High rates of sustained virologic response were observed among patients with hepatitis C virus (HCV) infection who received 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor ledipasvir. This study examined 8 weeks of treatment with this regimen. METHODS: In this phase 3, open-label study, we randomly assigned 647 previously untreated patients with HCV genotype 1 infection without cirrhosis to receive ledipasvir and sofosbuvir (ledipasvir-sofosbuvir) for 8 weeks, ledipasvir-sofosbuvir plus ribavirin for 8 weeks, or ledipasvir-sofosbuvir for 12 weeks. The primary end point was sustained virologic response at 12 weeks after the end of therapy. RESULTS: The rate of sustained virologic response was 94% (95% confidence interval [CI], 90 to 97) with 8 weeks of ledipasvir-sofosbuvir, 93% (95% CI, 89 to 96) with 8 weeks of ledipasvir-sofosbuvir plus ribavirin, and 95% (95% CI, 92 to 98) with 12 weeks of ledipasvir-sofosbuvir. As compared with the rate of sustained virologic response in the group that received 8 weeks of ledipasvir-sofosbuvir, the rate in the 12-week group was 1 percentage point higher (97.5% CI, -4 to 6) and the rate in the group that received 8 weeks of ledipasvir-sofosbuvir with ribavirin was 1 percentage point lower (95% CI, -6 to 4); these results indicated noninferiority of the 8-week ledipasvir-sofosbuvir regimen, on the basis of a noninferiority margin of 12 percentage points. Adverse events were more common in the group that received ribavirin than in the other two groups. No patient who received 8 weeks of only ledipasvir-sofosbuvir discontinued treatment owing to adverse events. CONCLUSIONS: Ledipasvir-sofosbuvir for 8 weeks was associated with a high rate of sustained virologic response among previously untreated patients with HCV genotype 1 infection without cirrhosis. No additional benefit was associated with the inclusion of ribavirin in the regimen or with extension of the duration of treatment to 12 weeks. (Funded by Gilead Sciences; ION-3 ClinicalTrials.gov number, NCT01851330.).

  PublisherOA PDFDOI

• Novel inflammatory biomarkers of portal pressure in compensated cirrhosis patients

  Hepatology · 2013-10-12 · 72 citations

  articleOpen accessSenior authorCorresponding

  UNLABELLED: The rationale for screening inflammatory serum biomarkers of the hepatic vein pressure gradient (HVPG) is based on the fact that portal hypertension is pathogenically related to liver injury and fibrosis, and that in turn these are associated with the activation of inflammatory pathways. This was a nested cohort study in the setting of a randomized, clinical trial to assess the development of gastroesophageal varices (GEV) (N Engl J Med 2005;353:2254). Patients had cirrhosis and portal hypertension but did not have GEV. A total of 90 patients who had baseline day-1 sera available were enrolled in the present study. The objective of this study was to determine whether inflammatory biomarkers in conjunction with clinical parameters could be used to develop a predictive paradigm for HVPG. The correlations between HVPG and interleukin (IL)-1β (P=0.0052); IL-1R-α (P=0.0085); Fas-R (P=0.0354), and serum VCAM-1 (P=0.0007) were highly significant. By using multivariate logistic regression analysis and selected parameters (transforming growth factor beta [TGFβ]; heat shock protein [HSP]-70; at-risk alcohol use; and Child class B) we could exclude HVPG ≥ 12 mmHg with 86% accuracy (95% confidence interval [CI]: 67.78 to 96.16%) and the sensitivity was 87.01% (95% CI: 69.68 to 96.34%). Therefore, the composite test could identify 86% of compensated cirrhosis patients with HVPG below 12 mmHg and prevent unnecessary esophagogastroduodenoscopy with its associated morbidity and costs in these patients. Our diagnostic test was not efficient in predicting HVPG ≥ 12 mmHg. CONCLUSION: A blood test for HVPG could be performed in cirrhosis patients to prevent unnecessary esophagogastroduodenoscopy.

  PublisherOA PDFDOI

• 190 AST-120 (SPHERICAL CARBON ADSORBENT) IN COVERT HEPATIC ENCEPHALOPATHY: RESULTS OF THE ASTUTE TRIAL

  Journal of Hepatology · 2013-04-01 · 19 citations

  articleOpen access
  PublisherOA PDFDOI

Recent grants

• NIH Grant R41HL122022

  NIH · $312k · 2016

• NIH Grant R01DK046971

  NIH · $2.8M · 2003

• NIH Grant R37DK046971

  NIH · $3.4M · 2013

• NIH Grant R01DK038652

  NIH · $4.9M · 2011

• Targeting C/EBP-beta Phosphorylation for the Treatment of Lung Fibrosis

  NIH · $316k · 2015–2017

Frequent coauthors

• Martina Buck

  54 shared

• David A. Brenner

  Discovery Institute

  29 shared

• Beverly Peterkofsky

  25 shared

• K Houglum

  21 shared

• P. Pockros

  Scripps Clinic

  20 shared

• Tarek Hassanein

  20 shared

• Douglas M. Heuman

  20 shared

• J Vierling

  St. Luke's Episcopal Hospital

  19 shared

Education

• M.D.

  University of California, San Diego

• B.S.

  University of California, San Diego