VLDL Biogenesis and Secretion: It Takes a Village.

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.

Loss of hepatic SMLR1 causes hepatosteatosis and protects against atherosclerosis due to decreased hepatic VLDL secretion.

BACKGROUND AND AIMS: The assembly and secretion of VLDL from the liver, a pathway that affects hepatic and plasma lipids, remains incompletely understood. We set out to identify players in the VLDL biogenesis pathway by identifying genes that are co-expressed with the MTTP gene that encodes for microsomal triglyceride transfer protein, key to the lipidation of apolipoprotein B, the core protein of VLDL. Using human and murine transcriptomic data sets, we identified small leucine-rich protein 1 ( SMLR1 ), encoding for small leucine-rich protein 1, a protein of unknown function that is exclusively expressed in liver and small intestine. APPROACH AND RESULTS: To assess the role of SMLR1 in the liver, we used somatic CRISPR/CRISPR-associated protein 9 gene editing to silence murine Smlr1 in hepatocytes ( Smlr1 -LKO). When fed a chow diet, male and female mice show hepatic steatosis, reduced plasma apolipoprotein B and triglycerides, and reduced VLDL secretion without affecting microsomal triglyceride transfer protein activity. Immunofluorescence studies show that SMLR1 is in the endoplasmic reticulum and Cis-Golgi complex. The loss of hepatic SMLR1 in female mice protects against diet-induced hyperlipidemia and atherosclerosis but causes NASH. On a high-fat, high-cholesterol diet, insulin and glucose tolerance tests did not reveal differences in male Smlr1 -LKO mice versus controls. CONCLUSIONS: We propose a role for SMLR1 in the trafficking of VLDL from the endoplasmic reticulum to the Cis-Golgi complex. While this study uncovers SMLR1 as a player in the VLDL assembly, trafficking, and secretion pathway, it also shows that NASH can occur with undisturbed glucose homeostasis and atheroprotection.

Managing of Dyslipidaemia Characterized by Accumulation of Triglyceride-Rich Lipoproteins.

PURPOSE OF REVIEW: The accumulation of triglyceride-rich lipoproteins (TRLs) in plasma in patients with familial chylomicronaemia syndrome (FCS) or severe hypertriglyceridemia is associated with an increased risk of potentially life-threatening pancreatitis. Elevated TRL levels have also been suggested to contribute to atherosclerotic cardiovascular disease (ASCVD). This review provides the latest progress that has been made in this field of research. RECENT FINDINGS: Apolipoprotein C-III and angiopoietin-like protein 3 play key roles in the metabolism of TRLs. Targeting their production in the liver or their presence in the circulation effectively reduces triglycerides in patients with FCS or severe hypertriglyceridemia. Attempts to reduce triglyceride synthesis in the small intestine have been halted. Early studies with a fibroblast growth factor 21 agonist have shown to reduce plasma triglycerides and hepatic steatosis and improve glucose homeostasis. New drugs have recently been shown to effectively reduce plasma triglycerides which render hope for treating the risk of pancreatitis. Studies that have just been initiated will learn whether this unmet clinical will be met. It is too early to evaluate the potential of these drugs to reduce the risk of atherosclerosis through the reduction of triglycerides.

Activation of human γδ T cells and NK cells by Staphylococcal enterotoxins requires both monocytes and conventional T cells.

Staphylococcal enterotoxins (SE) pose a great threat to human health due to their ability to bypass antigen presentation and activate large amounts of conventional T cells resulting in a cytokine storm potentially leading to toxic shock syndrome. Unconventional T- and NK cells are also activated by SE but the mechanisms remain poorly understood. In this study, the authors aimed to explore the underlying mechanism behind SE-mediated activation of MAIT-, γδ T-, and NK cells in vitro. CBMC or PBMC were stimulated with the toxins SEA, SEH, and TSST-1, and cytokine and cytotoxic responses were analyzed with ELISA and flow cytometry. All toxins induced a broad range of cytokines, perforin and granzyme B, although SEH was not as potent as SEA and TSST-1. SE-induced IFN-γ expression in MAIT-, γδ T-, and NK cells was clearly reduced by neutralization of IL-12, while cytotoxic compounds were not affected at all. Kinetic assays showed that unconventional T cell and NK cell-responses are secondary to the response in conventional T cells. Furthermore, co-cultures of isolated cell populations revealed that the ability of SEA to activate γδ T- and NK cells was fully dependent on the presence of both monocytes and αß T cells. Lastly, it was found that SE provoked a reduced and delayed cytokine response in infants, particularly within the unconventional T and NK cell populations. This study provides novel insights regarding the activation of unconventional T- and NK cells by SE, which contribute to understanding the vulnerability of young children towards Staphylococcus aureus infections.