Non-Alcoholic Fatty Liver Disease, the HEpatic Response to Oral Glucose, and the Effect of Semaglutide (NAFLD HEROES)

Background: In non-alcoholic fatty liver disease (NAFLD), fat accumulates in the liver and can cause damage. Researchers want to learn what causes the damage NAFLD, and to see if a medication can help. Objective: To find out how the liver in people with NAFLD responds to feeding, and how this relates to their response to the drug semaglutide. Eligibility: People with NAFLD and healthy volunteers ages 18 and older Design: Participants will be screened with: Medical history Physical exam Blood tests Imaging: A machine will take pictures of the participant s body. Within 2-8 weeks of enrollment, participants will stay in the clinic for several days. This includes: Blood, urine, heart, and imaging tests For NAFLD participants only: A needle-like device will remove a small biopsy of the liver and fatty tissue. Participants will be alone in a special room for 5 hours. They will breathe through a tube under the nostrils. They will have blood drawn several times. The baseline visit concludes participation for healthy volunteers but NAFLD participants will contine. About 6 weeks after discharge, participants will stay in the clinic again and repeat the tests. They will get their first semaglutide dose by injection. Participants will have visits weeks 1, 2, 4, 8, 12, 16, 20, and 24 of treatment. Visits include blood tests. Participants will inject semaglutide once a week at home. At week 30, participants will stay in the clinic again and repeat the tests. Participants will have a final visit 12 weeks after stopping treatment. This includes blood and urine tests. ...

* INCLUSION CRITERIA: 1. Male or female Aged \>= 18 years of age. 2. Histological evidence of hepatic steatosis on a liver biopsy within 12 months OR evidence of fatty liver disease, as documented by imaging (ultrasound, CT, MRI, MRI-PDFF, MR spectroscopy, or Fibroscan CAP \>= 285 db/M25) within 12 months. 3. Estimated average alcohol consumption \< 30 g/d for men or \< 20 g/d for women in the 6 months prior to enrollment and no binge-drinking behavior. 4. Ability of subject to understand and the willingness to sign a written informed consent document. Additional Inclusion Criteria for Treatment Phase 1. Presence of NAFLD (steatosis grade greater than or equal to 1 on NASH-CRN scoring scale) on baseline admission liver biopsy. 2. Liver fat content greater than or equal to 10% by 1H-MRS on initial admission. EXCLUSION CRITERIA: 1. Pregnant or breast-feeding 2. Chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV). Patients who were treated successfully for HCV and achieved sustained virological response can be eligible for enrollment \> 18 months after treatment cessation. Patients receiving antiviral therapy are ineligible. 3. HIV infection. 4. Concomitant liver disease such as autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, Wilson s disease, alpha-1 antitrypsin deficiency, hereditary hemochromatosis. 5. Presence of definite or probable drug-induced liver injury. In the case of lipid-lowering, anti-hypertensive or anti-diabetic medications that are suspected to cause aminotransferase elevation, patients will be eligible if treatment is associated with stable enzyme levels for at least 6 months. 6. Decompensated advanced liver disease, defined as direct bilirubin \> 0.5 g/dL, PT \> 18 , albumin \< 3 g/dL, MELD score \> 12 (applicable only in patients without Gilbert s syndrome), or history of ascites, encephalopathy, variceal bleeding, spontaneous bacterial peritonitis or liver transplant 7. Treatment with medications known to cause fatty liver disease such as atypical neuroleptics, tetracycline, methotrexate or tamoxifen 8. Uncontrolled hypo- or hyperthyroidism. 9. Thyroid nodules with ultrasonographic features suggestive of an increased risk of thyroid cancer per radiologist reporting (hypoechoic, microcalcifications, twinkling on B flow imaging, central vascularity, irregular margins, incomplete halo, nodule taller than wide and documented enlargement of a nodule), or nodules associated with an abnormal TSH (0.4 to 5 mU/L). 10. Active coronary artery disease, defined as persistent angina pectoris, reversible ischemia on cardiac stress test or imaging, or the presence of significant coronary artery disease on imaging or catheterization. Patients with coronary artery disease that was treated by angioplasty or bypass surgery may be eligible if they have no evidence of active disease \>= 1 year after intervention, can safely stop antiplatelet and anticoagulant medications before the performance of invasive procedures, and have adequate ventricular function as assessed by echocardiography or cardiology consultation. These patients will require cardiology consultation and clearance prior to enrollment. 11. Congestive heart failure. 12. Chronic kidney disease, with creatinine clearance \< 60 ml/min or eGFR \< 60/ml/min/m(2). 13. Uncontrolled diabetes mellitus with HbA1c \> 9% will exclude subjects. Patients with diabetes may be enrolled only if they have HbA1c \ 10% of current body weight, by following a different diet or exercise regimen over the study time period or recent (\10%). 29. The receipt of any investigational drug within 3 months prior to enrollment in this trial. 30. Assessment by the principal investigator that the subject will be unlikely to complete the study procedures, or that enrollment puts the subject at a significant risk unspecified by the criteria above. INCLUSION CRITERIA for Healthy Volunteers (arm C) 1. Male or female Aged greater than or equal to 18 years of age. 2. No evidence of hepatic steatosis by imaging or histology. 3. No history of known liver disease. 4. Individuals on regular systemic medications may be considered eligible, and their eligibility will be determined by the principal investigator. 5. BMI less than or equal to 25 kg/m2 6. Non-diabetic. 7. Normal transaminases (ALT less than or equal to 31 U/L for men or less than or equal to 19 U/L for women, and AST less than or equal to 30 U/L). 8. Fasting glucose less than or equal to 95 mg/dL. 9. Ability of subject to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA for Healthy Volunteers (arm C) 1. Pregnant or breastfeeding 2. Excessive alcohol consumption, defined as an average alcohol consumption over \> 1 drink per day over the past month 3. Assessment by the principal investigator that the subject is unsuitable for participation in the study or that enrollment puts the subject at significant risk.