Review

Microsomal triglyceride transfer protein

Hyperlipidemia predisposes individuals to cardiometabolic diseases, the most common cause of global mortality. Microsomal triglyceride transfer protein (MTP) transfers multiple lipids and is essential for the assembly of apolipoprotein B-containing lipoproteins. MTP inhibition lowers plasma lipids but causes lipid retention in the liver and intestine. Previous studies suggested two lipid transfer domains in MTP and that specific inhibition of triglyceride (TG) and not phospholipid (PL) transfer can lower plasma lipids without significant tissue lipid accumulation. However, how MTP transfers different lipids and the domains involved in these activities are unknown. Here, we tested a hypothesis that two different β-sandwich domains in MTP transfer TG and PL. Mutagenesis of charged amino acids in β2-sandwich had no effect on PL transfer activity indicating that they are not critical. In contrast, amino acids with bulky hydrophobic side chains in β1-sandwich were critical for both TG and PL transfer activities. Substitutions of these residues with smaller hydrophobic side chains or positive charges reduced, whereas negatively charged side chains severely attenuated MTP lipid transfer activities. These studies point to a common lipid transfer domain for TG and PL in MTP that is enriched with bulky hydrophobic amino acids. Furthermore, we observed a strong correlation in different MTP mutants with respect to loss of both the lipid transfer activities, again implicating a common binding site for TG and PL in MTP. We propose that targeting of areas other than the identified common lipid transfer domain might reduce plasma lipids without causing cellular lipid retention.

Molecular genetic testing of patients with hypobetalipoproteinemia may identify a genetic cause that can form the basis for starting proper therapy. Identifying a genetic cause may also provide novel data on the structure-function relationship of the mutant protein.

To identify a genetic cause of hypobetalipoproteinemia in a patient with levels of low density lipoprotein cholesterol at the detection limit of 0.1 mmol/l.

DNA sequencing of the translated exons with flanking intron sequences of the genes adenosine triphosphate-binding cassette transporter 1, angiopoietin-like protein 3, apolipoprotein B, apolipoprotein A1, lecithin-cholesterol acyltransferase, microsomal triglyceride transfer protein and proprotein convertase subtilisin/kexin type 9.

The patient was homozygous for mutation Q384K (c.1150C>A) in the apolipoprotein B gene, and this mutation segregated with hypobetalipoproteinemia in the family. Residue Gln₃₈₄ is located in the large lipid transfer module of apoB that has been suggested to be important for lipidation of apolipoprotein B through interaction with microsomal triglyceride transfer protein. Based on measurements of serum levels of triglycerides and apolipoprotein B-48 after an oral fat load, we conclude that the patient was able to synthesize apolipoprotein B-48 in the intestine in a seemingly normal fashion.

Our data indicate that mutation Q384K severely reduces the secretion of apolipoprotein B-100 in the liver without reducing the secretion of apolipoprotein B-48 in the intestine. Possible mechanisms for the different effects of this and other missense mutations affecting the large lipid transfer module on the two forms of apoB are discussed.

Familial Hypercholesterolemia (FH), an autosomal dominant genetic disease, is increasingly emerging as a global threat. To learn more about the development of FH, 1 617 papers about FH and related research were retrieved in the Web of Science Core Collection from 2011 to 2021. Then, these publications were scientometrically analyzed based on CiteSpace and VOSviewer in terms of spatiotemporal distribution, author distribution, subject categories, topic distribution, and references. The results showed that research on FH is at a stable stage. More FH research has been conducted in developed countries, implying the necessity for strengthening international cooperation and exchanges. We have obtained scholars, institutions, relevant journals, and representative literatures that play an important role in FH. The research direction of FH is on the mechanisms of FH and its complications, diagnosis, statin therapy, and new lipid-lowering drug therapy. Care is the research frontier in FH, and it is in an explosive period.

Parenteral nutrition (PN)-associated liver disease (PNALD) is a common and life-threatening complication of patients receiving PN. However, its definitive pathology remains unclear. Ubiquinone oxidoreductase core subunit S1 (NDUFS1), which is the largest core subunit of mitochondrial complex I, could alter the mitochondrial reactive oxygen species (ROS) formation. The purpose of this study was to investigate the role of NDUFS1 in the pathogenesis of PNALD and its underlying mechanism. We performed hepatic proteomics analysis of PNALD patients, and established a PNALD rat model to verify the role of oxidative stress, NDUFS1, pyrin inflammasome, and IL-1β in the progression of PNALD.

Proteomics analysis revealed the NDUFS1 expression was decreased in PNALD patients, and the differentially espressed proteins were involved in mitochondrial respiratory chain complex Ⅰ. Treatment with MitoQ or overexpression of NDUFS1 can alleviate the progression of PNALD by reducing oxidative stress. The expression of pyrin, caspase-1, and IL-1β was increased in PN rats. Pharmacological antagonism of pyrin by colchicine can alleviate liver injury and hepatic steatosis.

NDUFS1 prevents PNALD pathogenesis by regulating oxidative stress. Pyrin inflammasome and IL-1β may participate in the process of PNALD development by suppressing the transcription of MTTP and impairing the secretion of VLDL. Oxidative stress reduction may be employed as a strategy in the prevention and treatment of PNALD.

In vivo data on intestinal fat absorption in weanling piglets are scarce.

This study aimed to investigate the effect of weaning stress on intestinal fat absorption.

Eighteen 7-d-old sow-reared piglets (Duroc-Landrace-Yorkshire) were assigned to 3 groups (n = 6/group, 3 males and 3 females per group). Piglets were nursed by sows until 24 d of age (suckling piglets, S), or weaned at 21 d of age to a corn-soybean meal–based diet until 24 d (3 d postweaning, W3) or 28 d (7 d postweaning, W7) of age, respectively. Duodenum, jejunum, and ileum were collected to determine intestinal morphology and abundance of proteins related to fat absorption.

Compared with the S group, the W3 group had lower villus height (17–34%) and villus height to crypt depth ratio (13–53%), as well as 1–1.45 times greater crypt depth; these values were 1.18–1.31, 0.69–1.15, and 1.47–1.87 times greater in the W7 group than in the W3 group, respectively. Compared with the S group, weaning stress for both W3 and W7 groups reduced intestinal alkaline phosphatase activity (26–73%), serum lipids (26–54%), and abundances of proteins related to fatty acid transport [fatty acid transport protein 4 (FATP4) and intestinal fatty acid-binding protein (I-FABP)] and chylomicron assembly [microsomal triglyceride transfer protein (MTTP), apolipoprotein A-IV (APOA4), B (APOB), and A-I (APOA1)] in the duodenum and ileum (10–55%), as well as in the jejunum (25–85%). All these indexes did not differ between W3 and W7 groups. Compared with the S group, the W3 group had lower mRNA abundances of duodenal APOA4 and APOA1 (25–50%), as well as jejunal FATP4, IFABP, MTTP, APOA4, and APOA1 (35–50%); these values were 5–15% and 10–37% lower in the W7 group than in the W3 group, respectively.

Weaning stress in piglets attenuates the expression of intestinal proteins related to fatty acid transport (FATP4 and I-FABP) and chylomicron synthesis (APOA4).

Los triglicéridos (TG) son las moléculas más importantes para la reserva energética de nuestro organismo. Después de su síntesis hepática o intestinal a partir de los ácidos grasos son vehiculizados por los quilomicrones (QM) (origen intestinal) en el plasma o VLDL (origen hepático). Su catabolismo está determinado por la acción del complejo proteico de la lipoproteína lipasa (LPL) y de los receptores hepáticos encargados de su aclaramiento (RLDL y LRP-1). Las alteraciones en la producción o en el catabolismo se manifiestan como hipertrigliceridemia (HTG).

Las HTG se clasifican según su gravedad en leves-moderadas (150-885 mg/dl), graves (> 885 mg/dl) o muy graves (> 1.770 mg/dl). Atendiendo su etiología pueden ser primarias y secundarias. Entre las principales formas primarias destaca el síndrome quilomicronémico familiar (SQF), forma muy severa debido a mutaciones del gen LPL o de proteínas asociadas. La mayoría de las HTG se deben a una coincidencia de factores de predisposición genética y ambientales.

Triglycerides (TG) are the most important molecules for the energy reserve of our body. After their hepatic or intestinal synthesis from fatty acids, they are carried by chylomicrons (QM (intestinal origin) or VLDL (hepatic origin) in plasma. Their catabolism is determined by the action of the lipoprotein lipase protein complex (LPL) and the hepatic receptors (RLDL and LRP-1) are responsible for their clearance are. Changes in the production or catabolism leads to hypertriglyceridaemia (HTG). The HTG are classified according to severity as, mild-moderate (150-885 mg/dl), severe (>885 mg/dl), or very severe (>1770 mg/dl). They can be primary and secondary depending on origin. In the main primary form is highlighted Familial Chylomicronaemia Syndrome (CFS), a very severe form due to mutations in the LPL gene or associated proteins. Most HTG are due to a combination of genetic and environmental predisposing factors.