VLDL Biogenesis and Secretion: It Takes a Village

Abstract

The production and secretion of VLDLs (very-low-density lipoproteins) by hepatocytes has a direct impact on liver fat content, as well as the concentrations of cholesterol and triglycerides in the circulation and thus affects both liver and cardiovascular health, respectively. Importantly, insulin resistance, excess caloric intake, and lack of physical activity are associated with overproduction of VLDL, hepatic steatosis, and increased plasma levels of atherogenic lipoproteins. Cholesterol and triglycerides in remnant particles generated by VLDL lipolysis are risk factors for atherosclerotic cardiovascular disease and have garnered increasing attention over the last few decades. Presently, however, increased risk of atherosclerosis is not the only concern when considering today’s cardiometabolic patients, as they often also experience hepatic steatosis, a prevalent disorder that can progress to steatohepatitis and cirrhosis. This duality of metabolic risk highlights the importance of understanding the molecular regulation of the biogenesis of VLDL, the lipoprotein that transports triglycerides and cholesterol out of the liver. Fortunately, there has been a resurgence of interest in the intracellular assembly, trafficking, degradation, and secretion of VLDL by hepatocytes, which has led to many exciting new molecular insights that are the topic of this review. Increasing our understanding of the biology of this pathway will aid to the identification of novel therapeutic targets to improve both the cardiovascular and the hepatic health of cardiometabolic patients. This review focuses, for the first time, on this duality.

CLCC1 promotes hepatic neutral lipid flux and nuclear pore complex assembly

“…Similar to LDs, lipoproteins consist of a neutral lipid core encircled by a phospholipid membrane decorated with regulatory proteins such as apolipoprotein B (apoB). The initial formation of lipoproteins involves microsomal triglyceride transfer protein (MTP)-mediated transfer of TAG into the ER lumen 11 . Incubation of CLCC1 KO cells with the MTP inhibitor CP-346086 rescued the biogenesis of PLIN2-positive LDs ( Fig 3G , H ) and the amount of neutral lipids (marked by monodansylpentane) ( Fig 3I ).…”

“…The liver is a central site of lipid metabolism 6 , 10 . Fatty acids in liver hepatocytes may be used to generate triacylglycerol (TAG) that is stored in cytoplasmic LDs or packaged into very low-density lipoproteins (VLDLs) for secretion into circulation 6 , 10 , 11 . Altered storage and secretion of lipids can lead to the persistent buildup of hepatocyte LDs, a pathological hallmark of Metabolic dysfunction-associated fatty liver disease (MAFLD) 6 , 12 .…”

Examining the Pathogenesis of MAFLD and the Medicinal Properties of Natural Products from a Metabolic Perspective

“…Glycerol-3-Phosphate Acyl Transferase (GPAT) catalyzes the formation of lysophosphatidic acid (LPA) from lipoyl-CoA and glycerol-3-phosphate (G3P), which subsequently synthesize diethylene glycol (DG) by Acylglycerol-3-Phosphate Acyl Transferases (AGPATs), Phosphatidic Acid Phosphatases (PAPs) and ultimately synthesize TG through diacylglycerol acyltransferase (DGAT) [59]. TGs further serve as the core lipid component of VLDL (Figure 1) [60]. DGAT may serve as a promising therapeutic target for MAFLD [61].…”

Review article: Hepatic steatosis and its associations with acute and chronic liver diseases

“…Secretion of lipoproteins, a unique function of the liver, takes place through the secretory pathway, with lipid loading occurring in apolipoprotein B-100 or ApoB-100-containing precursors within the lumen of the endoplasmic reticulum (ER). 14,15 Apolipoprotein B transcripts are subject to RNA editing, resulting in the ApoB-48 isoform being produced in the intestines and incorporated into chylomicrons, whose remnants are taken up by the liver after passing through systemic circulation. 14,15 Beta oxidation of fat is regulated by the activity of acetyl CoA carboxylase 2 within the mitochondrion, whose product, malonyl CoA, inhibits carnitine acyltransferase 1.…”

“…14,15 Apolipoprotein B transcripts are subject to RNA editing, resulting in the ApoB-48 isoform being produced in the intestines and incorporated into chylomicrons, whose remnants are taken up by the liver after passing through systemic circulation. 14,15 Beta oxidation of fat is regulated by the activity of acetyl CoA carboxylase 2 within the mitochondrion, whose product, malonyl CoA, inhibits carnitine acyltransferase 1. Circulating fatty acids, mostly bound to albumin, can be taken up by hepatocytes using multiple protein transporters.…”