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Review
. 2024 Jan 19;134(2):226-244.
doi: 10.1161/CIRCRESAHA.123.323284. Epub 2024 Jan 18.

VLDL Biogenesis and Secretion: It Takes a Village

Willemien van Zwol  1 , Bart van de Sluis  1 , Henry N Ginsberg #  2 , Jan Albert Kuivenhoven #  1
Affiliations
Review

VLDL Biogenesis and Secretion: It Takes a Village

Willemien van Zwol et al. Circ Res. .

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.

Keywords: apolipoprotein B; dyslipidemia; fatty liver; hepatocytes; triglycerides.

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Conflict of interest statement

Disclosures None.

Figures

Figure 1.
Figure 1.. Major metabolic pathways involved in hepatic triglyceride metabolism.
The level of triglycerides that is stored in hepatic lipid droplets is determined by the balance of fatty acids incorporated into triglyceride and fatty acid utilization. Triglyceride synthesis requires fatty acids that can be taken-up as free fatty acids from the plasma; that are synthesized from acetyl-CoA by de novo lipogenesis; and that derive from the breakdown of triglycerides taken up as the major core lipid component of VLDL and chylomicron remnants. Utilization comprises fatty acid oxidization in mitochondria and peroxisomes, and fatty acids used to synthesize triglycerides that are incorporated into VLDL, which are secreted into the circulation. For simplicity, we have not depicted pathways that maintain hepatic homeostasis of cholesterol or phospholipid levels, as they play minor quantitative roles in the development of hepatic steatosis.
Figure 2.
Figure 2.. A cellular model of the hepatic VLDL assembly and secretion pathway, with a focus on recently discovered key players.
For clarity, the proteins are localized to subcellular regions where they have significant effects on apoB/VLDL, although this may not be the only locations where they reside. ApoB, the core protein of VLDL, is widely accepted to be produced constitutively. There is however, increasing evidence that gene expression is also regulated at mRNA level through e.g., human antigen R (HUR ), TIA1 Cytotoxic granule associated RNA binding protein like 1 (TIAL1) , VIGILIN and miRNAs. Note: In the nucleus we have depicted the Apob100mRNA editing enzyme (APOBEC1) to make clear that in mouse hepatocytes but not human hepatocytes, APOBEC1 generates apoB48 mRNA which encodes for a truncated (48%) portion of the full-length APOB100 protein. This means that wild-type mice produce both apoB48 and apoB100 containing lipoproteins in the liver. Some investigators, therefore, use liver-specific Apobec1−/− mice to simplify their studies. In the majority of studies with active APOBEC1, however, manipulation of the VLDL biogenesis machinery affects apoB100 to a much greater extent than apoB48. During translation, apoB crosses the ER membrane, facilitated by numerous chaperones* (co-translational translocation). During this process, apoB is lipidated by microsomal triglyceride transport protein (MTP) (co-translocational lipidation)., When folding of apoB is abnormal or when lipidation is inadequate, apoB will be ubiquitinylated followed by proteasomal degradation. This process is facilitated by numerous proteins involved in ER-associated degradation** (ERAD). Newly identified factors in this process include liver-specific zona pellucida domain-containing protein (LZP ) and murine double minute 2 (MDM2 ). MTP is essential for stabilization and initial lipidation of apoB to form nascent VLDL. The supply of lipids, mostly triglycerides, for the initial lipidation of apoB derives from de novo lipogenesis in the ER membrane. The figure illustrates that many other proteins are implicated in biogenesis of nascent lipid poor VLDL and its conversion to more mature, well-lipidated VLDL. Newly proposed players in the first steps of this pathway are an AAA+ ATPase called TORSINA (activated by lamina-associated polypeptide 1, LAP1 ), proline-rich acidic protein 1 (PRAP1 ), phospholipase A2, group XIIB (PLA2G12B ), ER lipid raft proteins 1 and 2 (ERLIN1/2 ), and transmembrane 6 superfamily member 2 (TM6SF2) . Triglycerides added during the later or second stage of lipidation of nascent are believed to derive from both the ER membrane and from lipid droplets in a process involving triglyceride hydrolase (TGH , ). Vacuole membrane protein 1 (VMP1 ,) and transmembrane protein 41b (TMEM41B ), have recently been identified as key molecules in the budding off of VLDL from the ER membrane into the ER lumen. For the subsequent transport of VLDL from the ER to the Golgi, a long list of proteins of the COPII trafficking machinery (SAR1B, SEC13/31 and SEC23/24), and those needed for the packaging of larger cargos (TANGO1 and TALI , KLHL12) haven been described, as well as small valosin-containing protein-interacting protein (SVIP ); reticulin 3 (RTN3 ), and several small Rab GTPases (RABs ,), with surfeit locus protein 4 (SURF4 ) as the most recent addition. The docking of VLDL transport vesicles at the Cis-Golgi is reported to be mediated through interactions with SNAREs . The Golgi is the site where VLDL may be subjected to sorting, glycosylation, and phosphorylation, as well as additional/final lipidation, but only very few investigations have been conducted with a focus on the role of the Golgi in VLDL maturation and secretion. SORTILIN1, which has been localized to several post-ER sites, including the Golgi, appears to regulate VLDL secretion by re-directing some particles for auto-lysosomal degradation ,. While reviewing the literature, the scarcity of information on VLDL processing in the Golgi, how VLDL leaves the Golgi, and is transported to the cell membrane for eventual secretion into the circulation was striking. * Chaperones involved in APOB stabilization/folding: = BIP, PDI, ERP57, ERP72, HSP110, Calreticulin, Calnexin, GRP94, Cyclophilin B, HSP70 and HSP90. ** proteins involved in ER associated degradation (ERAD) of APOB: DERLIN-1, GP78/AMFR, HRD1, HSP40, P97, P58IPK, SEC61, UBXD8.
Figure 3.
Figure 3.. A cellular model of ApoB lipidation in the ER.
In the outer leaflet of the hepatocyte ER, diacylglyceride acyltransferase 1 and 2 (DGAT1 and DGAT2), acyl acyl-CoA cholesterol acyltransferase (ACAT), and phosphatidylethanolamine N-methyltransferase (PEMT) synthesize the main lipid components of VLDL, e.g., triglycerides, cholesteryl esters, and phospholipids, respectively. Triglycerides are the most abundant lipid in VLDL and modulation of DGAT1 or DGAT2 has been shown to affect VLDL biology ,. More details and a working model of how these proteins synthesize and incorporate triglycerides in the ER can be found elsewhere . Changes in cholesterol esterification by ACAT are also known to affect apoB lipoprotein assembly and secretion by the liver (for review see ). The importance of the synthesis of phospholipids via the PEMT pathway for VLDL synthesis and secretion was described by Vance and colleagues –. The newly synthesized lipids are proposed to be present in lens-like structures between the inner and the outer leaflets of the ER membrane. In this position, they are accessible as substrates for the lipidation of apoB by MTP to form nascent VLDL. Recent studies have demonstrated roles for additional proteins, including PRAP1 , PLA2G12B , ERLIN1/2 , TM6SF2 ,, TORSINA and SMLR1 that we have tried to capture in a one scheme. In the figure, we have depicted these new factors in an arbitrary order as it is not known what the actual sequence of events is and whether these proteins act individually or in concert. Little is known about the role proline-rich acidic protein 1 (PRAP1), a new interacting partner of MTP . Phospholipase A2, group XIIB (PLA2G12B) is a catalytically inactive phospholipase that appears to play an important role in VLDL lipidation and secretion . The lipidation of VLDL in the ER has previously been shown to also require transmembrane 6 superfamily member 2 (TM6SF2) ,; loss of TM6SF2 function in humans results in steatotic liver disease and lower plasma lipids . More recently it has been shown that for TMSF62 to stabilize apoB it needs ER lipid raft associated proteins (ERLIN) 1 and 2 . Another factor which has previously been shown to play a role in making TG in cytosolic lipid droplets available for further lipidation of VLDL is cell death-inducing DFFA-like effector b (CIDEB) . CIDEB has also been described to regulate the transport of VLDL transport vesicles and we therefore also display this factor in Figure 4. Triglyceride hydrolase (TGH) has more recently been described to play a significant role in VLDL biogenesis in mice ,. It is proposed to make triglycerides from lipid droplets available for VLDL lipidation but it not clear whether the lipid droplets are in the ER lumen or the cytosol. Small leucine rich protein 1 (SMLR1) is the most recent addition to this scheme . This protein of unknown function is localized in the ER but also the Golgi, and loss of hepatic SMLR1 results in hepatic steatosis and reduced VLDL secretion in mice, but its exact role has yet to be determined . The loss of hepatic TORSINA, has also been shown to induce the latter phenotype . It is a soluble ER protein that localizes to co-activators at the inner nuclear envelope and possibly the ER membrane, but how TORSINA affects the VLDL biogenesis machinery is as of yet not known.
Figure 4.
Figure 4.. A cellular model of VLDL recruitment to the ER exit site for VLDL transport vesicle formation.
Nascent VLDL is suggested to first bud off from the inner leaflet of the ER membrane to reach the lumen, of the ER after which it exits the ER to move to the Golgi and then the cytoplasm. For clarity we show these steps in different regions of the ER membrane, but the exact sites of these steps in VLDL trafficking are unknown. We have also left out all the lipidation steps to make the depiction on these trafficking processes easier to visualize. Vacuolar protein 1 (VMP1) and transmembrane protein 41B (TMEM41B), have recently been shown to mediate this step in VLDL biogenesis ,. Trafficking of VLDL from the ER lumen to the Golgi, requires the insertion of VLDL into COPII vesicles (for review see ). A key role for Ras related GTPase1B (SAR1B) in this process is illustrated by patients suffering from chylomicron retention disease but who also have reduced VLDL secretion and hepatic steatosis . The large size of the VLDL cargo, however, requires specialized, large vesicles that are formed with the help of TANGO and TALI . These proteins recruit VLDL to ER exit sites and allow fusion of VLDL with ERGIC membrane to generate an export pathway . Kelch-like protein 12 (KLHL12), another protein known to assist the transport of larger cargos in COPII vesicles, has previously also been shown to affect apoB/VLDL in McArdle RH-7777 cells . SURF4 has most recently been shown to also be involved in the exit of VLDL from the ER. The absence of SURF4 in the liver of mice was shown to result in hepatic steatosis with accumulation of VLDL in the ER lumen. In addition, Reticulon 3 (RTN3), has been shown to be involved in the transport of VLDL transport vesicles . Several RABs such as RAB1b, RAB23, and RAB24 have been shown to affect apoB/VLDL in both cell culture and experimental mouse studies ,. GP73 is a Golgi-resident protein but is thought to affect VLDL metabolism via RAB23 .
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