Effects of ACC Inhibitor on Lipid and Lipoprotein Metabolism

Inclusion Criteria: * Body mass index (BMI) of ≥ 25 kg/m2 but \< 40 kg/m2 and at least 2 of 5 traits of metabolic syndrome (fasting blood glucose \>100 mg/dl or diagnosis of diabetes mellitus; BP \>130/85; fasting TG \>150 mg/dl; HDL cholesterol \<40 mg/dl for men and \<50 mg/dl for women; waist circumference \>101 cm for men and \>89 cm for women). * NASH will be defined as a FibroScan® of CAP \>280 db/m and \>7 kPa, OR demonstrated by liver biopsy, plus: * ALT \> ULN but \< 5 X ULN. * FIB4 score \<3.5 (see below) * BP of ≤ 160/100 mmHg. * Alkaline phosphatase ≤ ULN. * Total bilirubin ≤ ULN (unless the subject has Gilbert's syndrome, a benign genetic problem where bilirubin is not conjugated normally and indirect bilirubin (unconjugated bilirubin increases) in which case direct bilirubin must be ≤ ULN with total bilirubin \> ULN). * Platelet count ≥ LLN (155,000/mm3). * Albumin ≥ LLN (3.0 g/L). * INR ≤ 1.3. * Fasting serum triglycerides ≤ 350 mg/dL either non-pharmacologically managed or pharmacologically managed with stable doses of up to 3 oral agents for at least 6 months. They may be receiving statins if the dose has been stable for at least 3 months. * Subjects may have diabetes but must have an HbA1C ≤ 8.0% with glycemic control either non-pharmacologically managed or pharmacologically managed with stable doses of up to 3 oral agents for at least 6 months. Subjects taking a stable dose of long-acting insulin or an injectable GLP-1 inhibitor may be enrolled at the discretion of the investigators. * No changes in drugs affecting blood lipid or glucose or insulin levels will be permitted during the study without approval by the investigators. Exclusion Criteria: * Individuals with a history of plasma TG \>1000 mg/dl and/or pancreatitis. * Females of childbearing potential. * Chronic kidney disease defined by estimated glomerular filtration rate \< 30 ml/min/1.73 m² by the modification of diet in renal disease equation. * Documented chronic hepatitis B or C. Subjects with hepatitis C are eligible provided there is proof of sustained virology response (SVR) for ≥ 3 years. * History of active malignancy within 5 years (subjects with non-melanoma skin cancer may be included). * Any other disease, condition, or laboratory value that, in the opinion of the principal investigator or clinical study team would place the subject at an unacceptable risk or interfere with the evaluation of the investigative product. * History of organ transplantation (other than corneal). * History of hepatobiliary malignancy even if subject "cured". * Pancreas divisum or a congenital abnormality of the pancreas * History of pancreatic surgery. * Subjects taking anti -coagulants or anti-platelet agents other than 81 mg ASA daily. * Treatment with immunomodulators. * Drugs associated with acute pancreatitis as asparaginase, azathioprine, didanosine, mecaptourinol, mesalamine, opiates, pentamidine, pentavalent anti-monials, valproic acid, and rifampin. * OATP inhibitors such as gemfibrozil and cyclosporinea. Drugs substrates for CYP3A4/5 with a narrow therapeutic index - these include: alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, and terfenadine will be reason for exclusion. a = the major clearance mechanism of PF-05221304 is active uptake into liver (mainly via hepatic transporters OATP1B1/1B3) followed by hepatic carbonyl reductase 1, 11b-hydroxysteroid dehydrogenase, and CYP 3A4/5-mediated metabolism. It is anticipated that potent OATP inhibitors may increase plasma concentrations of PF-05221304. As such, subjects treated with clinically relevant OATP inhibitors will be excluded from this study.