Effect of Heavy Alcohol Consumption on Farnesoid X Receptor (FXR) Signaling

Not Applicable

Completed

Brief Summary: The main purpose of this study is to see whether heavy drinking will interfere with a specific pathway, called FXR signaling in the liver. The abnormality of this pathway may lead to liver injury in some patients who drink heavily.

Recruitment & Eligibility

Inclusion Criteria

Individuals ≥ 21 to 65 years old
Able to provide informed consent & negative urine pregnancy test where appropriate
Healthy controls must have not consumed any alcohol within 3 months prior to the screening visit
Heavy alcohol drinking is defined as > 40 grams per day on average in women and > 60 grams per day on average in men for a minimum of 6 months
Women of child bearing potential should be willing to practice contraception throughout the treatment period

Exclusion Criteria

Active infection as evidenced by positive urine culture, blood culture, or pneumonia
Serum creatinine > 1.5 mg/dL
Known co-existing infection with hepatitis C, hepatitis B, or HIV
Significant systemic or major illness including COPD, CHF and renal failure that in the opinion of the Investigator would preclude the patient from participating in and completing the study.
Participation in another investigational drug, biologic, or medical device trial within 30 days prior to Screening
Previous history of jaundice or signs of liver diseases such as spider angiomata, ascites, or history of esophageal varices or hepatic encephalopathy
Total bilirubin > 2 mg/dl and INR > 1.5 Page 20 of 37
Women who are pregnant or nursing
Presence of any other disease or condition that is interfering with the absorption, distribution, metabolism, or excretion of drugs including bile salt metabolism in the intestine. Patients who have undergone gastric bypass procedures will be excluded (gastric lap band is acceptable).
Subjects who are taking warfarin

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Heavy Drinkers on placebo
10 mg Obeticholic Acid (OCA)	10 mg Obeticholic Acid (OCA)	10 mg Obeticholic Acid (OCA) Study medication will be administered orally, once daily for 4 weeks.

Primary Outcome Measures

Name	Time	Method
Change in Bile Salt Metabolism (C4 )Levels to Determine Effect of FXR	Baseline to 28 days
Change in FGF19 Levels to Determine Effect of FXR	Baseline to 28 days

Secondary Outcome Measures

Name	Time	Method
Change in Fasting Serum Bile Salt Levels	Baseline to 28 days
Change in CYP2E1 Activity by Measuring Chlorzoxazone Clearance	Baseline to 28 days
Change in Activation of Innate Immunity Through Measures of IL-6	Baseline to 28 days
Change in Intestinal Inflammation by Measuring Stool Calprotectin	Baseline to 28 days
Change in Activation of Innate Immunity Through Measures of IL-8	Baseline to 28 days
Change in Activation of Innate Immunity Through Measures of IL-1	Baseline to 28 days
Change in Oxidative Stress Level by Measuring Malondialdehyde	Baseline to 28 days
Change in Gut Permeability Through Lactulose/Mannitol Test	Baseline to 28 days	This is the measurement to quantify two non-metabolized sugar molecules-lactulose and mannitol-to determine the gut permeability
Change in Bacterial Translocation Through Measures of Plasma LPS	Baseline to 28 days
Change in Bacterial Translocation Through Measures of Serum sCD14	Baseline to 28 days
Change in Activation of Innate Immunity Through Measures of TNF-alpha	Baseline to 28 days