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

* 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 \<=9%, have been on stable therapy with lifestyle and/or metformin for at least 3 months prior to enrollment, and are not foreseen to require change of antidiabetic medication or dose during the trial. 14. Use of insulin, sulfonylurea agents, thiazolidinediones, SGLT2 inhibitors, GLP-1 receptor agonists or DPP-4 inhibitors unless discontinued greater than or equal to 3 months before enrollment. 15. Contraindication or inability to perform a liver biopsy. 1. Patients with coagulopathy (PT/PTT values that are prolonged greater than or equal to 3 seconds from the upper limit of the normal, including treatment with oral and parenteral anticoagulants), thrombocytopenia (\< 70,000), abnormal bleeding time or platelet dysfunction. Antiplatelet agents taken for cardiovascular prevention will not exclude patients, unless they cannot be stopped safely for the performance of a liver biopsy. 2. Hemoglobin level \< 11 g/dL 16. Contraindications to MRI (heart pacemakers, unless MRI safe, insulin pumps, implanted hearing aids, neurostimulators, intracranial metal clips, metallic bodies in the eye, metal hip replacements, sutures, extreme anxiety or fear of small spaces.) 17. History of gastric bypass or other bariatric surgery, partial or complete gastrectomy and known maldigestion or malabsorption. 18. Treatment with orlistat. 19. Patients with uncontrolled eating disorders including anorexia and bulimia nervosa. 20. Patients with proliferative diabetic retinopathy. 21. Use of medications or supplements to treat NAFLD (approved or unapproved) unless withdrawn greater than or equal to 3 months prior to enrollment or taken at a stable dose for greater than or equal to 6 months. 22. Patients who had a liver biopsy performed less than or equal to 2 years before enrollment, unless they are willing to undergo all of the trial biopsies, knowing that these biopsies are purely for research and are not clinically indicated. This will be clearly documented in the patients charts prior to enrollment. 23. Inability or unwillingness to receive subcutaneous injections. 24. Known or suspected allergy to trial medication(s), excipients, or related products. 25. Alcohol or substance abuse within the past 12 months. 26. For women of childbearing potential, breast-feeding, pregnancy or inability or unwillingness to practice contraception for the duration of the study. 27. Personal or first-degree family member with history of medullary thyroid carcinoma or subjects with known multiple endocrine neoplasia syndrome type 2 (MEN-2). 28. Actively pursuing an intensive weight loss regiment, aimed at losing \> 10% of current body weight, by following a different diet or exercise regimen over the study time period or recent (\<3 months) significant weight loss (\>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.