Question

A 53-year-old male with past medical history of obesity (BMI of 38 kg/m 2 ) and borderline diabetes presents to you with abnormal liver enzymes (ALT/AST) discovered 6 months ago. His family history is significant for liver cirrhosis. On physical examination you notice mild hepatomegaly (enlarged liver). A panel of lab tests revealed the following: aspartate aminotransferase (AST) 106 (normal range 10 – 40 U/L), alanine aminotransferase (ALT) 118 (normal range 7 – 56 U/L), with normal bilirubin (generated from the breakdown of hemoglobin). He had a liver ultrasonography that showed diffuse increase in echogenicity and vascular blurring consistent with fatty infiltration. You suspect nonalcoholic fatty liver disease (NAFLD). Under normal conditions, describe the metabolism and maturation of VLDL particles. Describe how NAFLD could manifest and what potential processes could be impaired in order for this disease process to occur (consider both enzymatic and hormonal impairments).

Answer 1

VLDL or very low-density lipoprotein is made by the liver. VLDL is assembled in the liver from triglycerides, cholesterol and apolipoprotein. Nascent VLDL released from the liver contains apolipoprotein B100, apolipoprotein C1 (apoC1), apolipoprotein E (apoE), cholesterol, cholesteryl esters, and triglycerides. As it circulates in the blood, it picks up apolipoprotein C-II (apoC-II) and additional apoE donated from high-density lipoprotein (HDL). At this point, nascent VLDL becomes a mature VLDL. Now as soon as it comes in contact with lipoprotein lipase removal of triglycerides occur for storage or energy production. Now VLDL devoid of its triglycerides meets HDL  where apoC-II is transferred back to HDL. HDL also transfers cholesteryl esters to the VLDL in exchange for phospholipids and triglycerides via cholesteryl ester transfer protein (CETP). Finally, VLDL becomes intermediate density lipoprotein (IDL) by the removal of more and more triglycerides.

50% of IDL  are recognized by receptors in the liver cells because of the apolipoprotein B-100 and apoE. the other 50% of IDL lose apoE; when their cholesterol content becomes greater than the content of triglyceride, they become LDL (low density lipoprotein). The LDL is taken into a cell via the LDL receptor via endocytosis, where the contents are either stored, used for cell membrane structure, or converted into other products such as steroid hormones or bile acids.

Accumulation of free fatty acids and triglycerides in the liver due to insulin resistance and obesity gives rise to NAFLD. It is considered the hepatic manifestation of the metabolic syndrome, a combination of medical conditions including type 2 diabetes mellitus, hypertension, hyperlipidemia, and visceral adiposity.