StAR-related lipid transfer protein 4 (STARD4) is a soluble protein involved in cholesterol transport. It can transfer up to 7 sterol molecules per minute between artificial membranes. [5]
StAR-related lipid transfer protein 4 (STARD4) is a soluble protein involved in cholesterol transport. It can transfer up to 7 sterol molecules per minute between artificial membranes. [5]
STARD4 may regulate cholesterol levels in many cells, including in the liver. STARD4 has specifically been linked to the movement of cholesterol to the endoplasmic reticulum. The protein is associated with the endoplasmic reticulum and lipid droplets. [6] Increases in the protein relate to cell stress. [7]
High levels of STARD4 increases the synthesis of bile acids and cholesterol esters in liver hepatocytes. [8] Reductions in cholesterol synthesis by cells increase STARD4 levels while StarD4 declines in mice fed a high cholesterol diet. [9] [10]
Increases in levels of either master gene regulator SREBP-1a or SREBP2, which both promote the production of proteins involved in cholesterol synthesis, increase StarD4 levels in mouse liver. [11] Conversely, increased STARD4 increases active SREBP2 levels.
Loss of the protein in mice has little effect. [12] Mice without functional STARD4 weigh less and females tend to have lower cholesterol profiles. The most dramatic change observed to date is a reduction in NPC-1, a protein involved in bringing cholesterol into cells.
The protein is 205 amino acids long in the human (224 in the mouse) and almost entirely consists of a StAR-related transfer (START) domain. It also lends its name to the subgroup of START domain proteins it is part of, StarD4. This subfamily includes STARD5 and STARD6 and is closely related to the StarD1/D3 group.
HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. Normally in mammalian cells this enzyme is suppressed by cholesterol derived from the internalization and degradation of low density lipoprotein (LDL) via the LDL receptor as well as oxidized species of cholesterol. Competitive inhibitors of the reductase induce the expression of LDL receptors in the liver, which in turn increases the catabolism of plasma LDL and lowers the plasma concentration of cholesterol, which is considered, by those who accept the standard lipid hypothesis, an important determinant of atherosclerosis. This enzyme is thus the target of the widely available cholesterol-lowering drugs known collectively as the statins.
Michael Stuart Brown ForMemRS is an American geneticist and Nobel laureate. He was awarded the Nobel Prize in Physiology or Medicine with Joseph L. Goldstein in 1985 for describing the regulation of cholesterol metabolism.
Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes SREBF1 and SREBF2. SREBPs belong to the basic-helix-loop-helix leucine zipper class of transcription factors. Unactivated SREBPs are attached to the nuclear envelope and endoplasmic reticulum membranes. In cells with low levels of sterols, SREBPs are cleaved to a water-soluble N-terminal domain that is translocated to the nucleus. These activated SREBPs then bind to specific sterol regulatory element DNA sequences, thus upregulating the synthesis of enzymes involved in sterol biosynthesis. Sterols in turn inhibit the cleavage of SREBPs and therefore synthesis of additional sterols is reduced through a negative feed back loop.
The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors, however, upon discovery of endogenous oxysterols as ligands, they were subsequently deorphanized.
Cholesterol 7 alpha-hydroxylase also known as cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1) is an enzyme that in humans is encoded by the CYP7A1 gene which has an important role in cholesterol metabolism. It is a cytochrome P450 enzyme, which belongs to the oxidoreductase class, and converts cholesterol to 7-alpha-hydroxycholesterol, the first and rate limiting step in bile acid synthesis.
Squalene synthase (SQS) or farnesyl-diphosphate:farnesyl-diphosphate farnesyl transferase is an enzyme localized to the membrane of the endoplasmic reticulum. SQS participates in the isoprenoid biosynthetic pathway, catalyzing a two-step reaction in which two identical molecules of farnesyl pyrophosphate (FPP) are converted into squalene, with the consumption of NADPH. Catalysis by SQS is the first committed step in sterol synthesis, since the squalene produced is converted exclusively into various sterols, such as cholesterol, via a complex, multi-step pathway. SQS belongs to squalene/phytoene synthase family of proteins.
Squalene monooxygenase is an enzyme that uses NADPH and molecular oxygen to oxidize squalene to 2,3-oxidosqualene. Squalene epoxidase catalyzes the first oxygenation step in sterol biosynthesis and is thought to be one of the rate-limiting enzymes in this pathway. In humans, squalene epoxidase is encoded by the SQLE gene. Several eukaryote genomes lack a squalene monooxygenase encoding gene, but instead encode an alternative squalene epoxidase that catalyzes the oxidation of squalene.
Sterol regulatory element-binding protein cleavage-activating protein, also known as SREBP cleavage-activating protein or SCAP is a protein that in humans is encoded by the SCAP gene.
Sterol regulatory element-binding transcription factor 1 (SREBF1) also known as sterol regulatory element-binding protein 1 (SREBP-1) is a protein that in humans is encoded by the SREBF1 gene.
Sterol regulatory element-binding protein 2 (SREBP-2) also known as sterol regulatory element binding transcription factor 2 (SREBF2) is a protein that in humans is encoded by the SREBF2 gene.
Membrane-bound transcription factor site-1 protease, or site-1 protease (S1P) for short, also known as subtilisin/kexin-isozyme 1 (SKI-1), is an enzyme that in humans is encoded by the MBTPS1 gene. S1P cleaves the endoplasmic reticulum loop of sterol regulatory element-binding protein (SREBP) transcription factors.
Sterol O-acyltransferase 1, also known as SOAT1, is an enzyme that in humans is encoded by the SOAT1 gene.
Insulin induced gene 1, also known as INSIG1, is a protein which in humans is encoded by the INSIG1 gene.
Sterol O-acyltransferase 2, also known as SOAT2, is an enzyme that in humans is encoded by the SOAT2 gene.
Oxysterol-binding protein 1 is a protein that in humans is encoded by the OSBP gene.
Insulin induced gene 2, also known as INSIG2, is a protein which in humans is encoded by the INSIG2 gene.
StAR-related lipid transfer protein 5 is a protein that in humans is encoded by the STARD5 gene. The protein is a 213 amino acids long, consisting almost entirely of a StAR-related transfer (START) domain. It is also part of the StarD4 subfamily of START domain proteins, sharing 34% sequence identity with STARD4.
CYP8B1 also known as sterol 12-alpha-hydroxylase is a protein which in humans is encoded by the CYP8B1 gene.
Methylsterol monooxygenase 1 is a protein that in humans is encoded by the MSMO1 gene.
StAR related lipid transfer domain containing 3(STARD3) is a protein that in humans is encoded by the STARD3 gene. STARD3 also known as metastatic lymph node 64 protein (MLN64) is a late endosomal integral membrane protein involved in cholesterol transport. STARD3 creates membrane contact sites between the endoplasmic reticulum and late endosomes where it moves cholesterol.