In liver, the synthesis of cholesterol and fatty acids increases in response to cholesterol deprivation and insulin elevation, respectively. This regulatory mechanism underlies the adaptation to cholesterol synthesis inhibitors (statins) and high calorie diets (insulin). In nonhepatic cells, lipid synthesis is controlled by sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors whose active domains are released proteolytically to enter the nucleus and activate genes involved in the synthesis and uptake of cholesterol and fatty acids. SCAP (SREBP cleavage-activating protein) is a sterol-regulated escort protein that transports SREBPs from their site of synthesis in the endoplasmic reticulum to their site of cleavage in the Golgi. Here, we produced a conditional deficiency of SCAP in mouse liver by genomic recombination mediated by inducible Cre recombinase. SCAP-deficient mice showed an 80% reduction in basal rates of cholesterol and fatty acid synthesis in liver, owing to decreases in mRNAs encoding multiple biosynthetic enzymes. Moreover, these mRNAs failed to increase normally in response to cholesterol deprivation produced by a cholesterol synthesis inhibitor and to insulin elevation produced by a fasting-refeeding protocol. These data provide in vivo evidence that SCAP and the SREBPs are required for hepatic lipid synthesis under basal and adaptive conditions.

Previous studies have shown that the rate of fatty acid synthesis is elevated by more than 20-fold in livers of transgenic mice that express truncated nuclear forms of sterol regulatory element-binding proteins (SREBPs). This was explained in part by an increase in the levels of mRNA for the two major enzymes of fatty acid synthesis, acetyl-CoA carboxylase and fatty acid synthase, whose transcription is stimulated by SREBPs. Fatty acid synthesis also requires a source of acetyl-CoA and NADPH. In the current studies we show that the levels of mRNA for ATP citrate lyase, the enzyme that produces acetylCoA, are also elevated in the transgenic livers. In addition, we found marked elevations in the mRNAs for malic enzyme, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase, all of which produce NADPH. Finally, we found that overexpressing two of the SREBPs (1a and 2) led to elevated mRNAs for stearoyl-CoA desaturase 1 (SCD1), an isoform that is detectable in nontransgenic livers, and SCD2, an isoform that is not detected in nontransgenic livers. This stimulation led to an increase in total SCD activity in liver microsomes. Together, all of these changes would be expected to lead to a marked increase in the concentration of monounsaturated fatty acids in the transgenic livers, and this was confirmed chromatographically. We conclude that expression of nuclear SREBPs is capable of activating the entire coordinated program of unsaturated fatty acid biosynthesis in mouse liver. Sterol regulatory element-binding proteins (SREBPs)1 are a family of transcription factors that regulate the low density lipoprotein (LDL) receptor and multiple enzymes required for the biosynthesis of cholesterol and fatty acids (see Ref. 1 for review). SREBPs belong to the basic helix-loop-helix leucine zipper family of transcription factors. Unlike other members of the basic helix-loop-helix leucine-Zip family, SREBPs are synthesized as ϳ1150 amino acid precursors bound to the endoplasmic reticulum and nuclear envelope. The membrane-bound precursor must undergo a sequential two-step cleavage process to release the transcriptionally active NH 2 -terminal portion of the protein (2). Once cleaved, the ϳ500 amino acid NH 2 -terminal nuclear form enters the nucleus and activates transcription by binding to promoter regions of genes containing non-palindromic sterol regulatory elements as well as palindromic sequences called E-boxes (1,3,4). Genes involved in cholesterol metabolism that are directly activated by SREBPs include the LDL receptor, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase, HMG-CoA reductase, farnesyl diphosphate synthase, squalene synthase, and SREBP-2 (1, 5-8). Genes involved in fatty acid and triglyceride synthesis, including acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and glycerol-3-phosphate acyltransferase (GPAT), are also directly activated by SREBPs (9 -11).To date, three isoforms of SREBP have been identified and characterized (1). The human versions of all three isoforms were originally d...

No abstract

We report two fatal cases of rhino-orbital-cerebral mucormycosis associated with COVID-19 infection. Both patients had pre-existing diabetes mellitus type 2, were treated with corticosteroids, and developed ketoacidosis. Both patients rapidly declined owing to rapid extension of the infection into the intracranial cavity. We postulate that additional risk factors for opportunistic fungal infection exist in COVID-19 patients including mechanical ventilation and Sars-CoV-2 induced immunosuppression. The ophthalmologist's role is particularly important in the early diagnosis of mucormycosis associated with COVID-19.