Lipoprotein metabolism in nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD), an escalating health problem worldwide, covers a spectrum of pathologies characterized by fatty accumulation in hepatocytes in early stages, with potential progression to liver inflammation, fibrosis, and failure. A close, yet poorly understood link exists between NAFLD and dyslipidemia, a constellation of abnormalities in plasma lipoproteins including triglyceride-rich very low density lipoproteins. Apolipoproteins are a group of primarily liver-derived proteins found in serum lipoproteins; they not only play an extracellular role in lipid transport between vital organs through circulation, but also play an important intracellular role in hepatic lipoprotein assembly and secretion. The liver functions as the central hub for lipoprotein metabolism, as it dictates lipoprotein production and to a significant extent modulates lipoprotein clearance. Lipoprotein metabolism is an integral component of hepatocellular lipid homeostasis and is implicated in the pathogenesis, potential diagnosis, and treatment of NAFLD.

Keywords: apolipoprotein; hepatic steatosis; lipoprotein metabolism; nonalcoholic fatty liver disease (NAFLD); nonalcoholic steatohepatitis; very low density lipoprotein.

Fig. 1. Overview of lipoprotein metabolism.

Human lipoproteins are predominantly produced by the small intestine and the liver. Small intestine produces chylomicron, which contains apoB48, apoA-I, apoC-I, apoC-II, and apoC-III. The remnant particles, after utilization of lipids by the peripheral tissue, are taken up by the hepatocytes. The liver produces apoB-100-containing VLDL and premature HDL. VLDL is hydrolyzed in circulation and converted into IDL and LDL. Both IDL and LDL can be taken up by the hepatocytes. The discoidal shaped premature HDL becomes mature HDL in the circulation, and serves an important role in reverse cholesterol transport. VLDL: very low density lipoprotein; HDL: high density lipoproteins; IDL: intermediate density lipoprotein; LDL: low density lipoprotein.

Fig. 2. VLDL synthesis in hepatocytes.

VLDL synthesis requires a synchronized process along apoB-100 maturation in the ER-Golgi secretory compartments. The nascent apoB-100 forms a primordial particle within the ER with the assistance of MTP. The primordial particle subsequently expands as the translation of apoB continues and more lipids are added. Intralumenal lipid droplets are also formed within the ER, and carry apoC-III. The VLDL precursor will combine with the intralumenal lipid droplets, either in the ER or in the Golgi, through a process that may or may not require the MTP activity. Mature VLDLs are secreted through vesicle-mediated exocytosis. PM: plasma membrane; VLDL: very low density lipoprotein; ER: endoplasmic reticulum; MTP: microsomal triglyceride-transfer protein.

Fig. 3. Predicted natural history of serum lipoprotein levels in NAFLD.

NAFLD is associated with dyslipidemia, an integral feature of metabolic syndrome. As disease progresses, hepatic lipoprotein production will decline as a result of decompensated liver failure. This progression may be manifested as a decline in serum lipoprotein levels, which may potentially precede global decline in hepatic synthetic function, a condition currently monitored by albumin and coagulation time clinically. NAFLD: non-alcoholic fatty liver disease.

Fig. 4. Lipid homeostasis in normal state (A) vs insulin resistance state (B).

The flow of lipids among different organs is shown schematically. The pointed-arrow depicts the direction of lipid flow; the line thickness and grayscale represent the relative quantity. The arrow with open circle indicates factors mediating the lipid delivery. In normal lipid homeostasis, dietary lipids are excreted with apoB-48 in the forms of chylomicrons from the small intestine. The majority of this lipid load is utilized by peripheral tissues (e.g. adipocytes and skeletal muscles). A portion of this lipid load reaches the liver via apoE mediated uptake. Under insulin resistance conditions, besides increased FFA release from adipocytes, decreased LPL activity shunts more lipid load away from the peripheral tissues toward ectopic organs such as the liver and the pancreas. Hepatic steatosis is a high lipid turnover state, a condition associated with increased uptake and secretion of lipoproteins. Fatty deposition in islet cells further exacerbates metabolic syndrome. VLDL: very low density lipoprotein; FFA: free fatty acid; LPL: lipoprotein lipase.