Biology subjects

Widenmaier, S. B.

Publications and source records attributed to Widenmaier, S. B..

3 recordsLinked to original sources

bioRxiv2024

Control of cholesterol-induced adipocyte inflammation by the Nfe2l1-Atf3 pathway

While adipocytes are critical pillars of energy metabolism, their dysfunction is linked to adipose tissue (AT) inflammation, insulin resistance, and ectopic lipotoxicity in cardiometabolic diseases. However, the mechanisms causing adipocyte inflammation and insulin resistance remain unclear. Here, we show that excess cholesterol induces adipocyte dysfunction, which is suppressed by the transcription factor Nfe2l1 (nuclear factor erythroid derived-2, like-1). Nfe2l1 is required to sustain proteasome function in adipocytes and proteotoxic stress induces adipocyte inflammation via the activation of Atf3. In humans, the Nfe2l1-proteasome pathway is inversely correlated to body mass index (BMI) in an adipose-depot specific manner. In mice, loss of adipocyte Nfe2l1 caused AT inflammation with a pronounced infiltration of macrophages and T cells. Mice lacking adipocyte Nfe2l1 displayed severe adipocyte dysfunction during diet-induced obesity (DIO), characterized by lower adipokine levels, steatosis, glucose intolerance and insulin resistance. Nfe2l1{Delta}AT mice on an Apoe-deficient (Apoe-/-) background fed a cholesterol-rich Western Diet (WD), developed a lipoatrophy-like syndrome, dyslipidemia, and enhanced atherosclerosis. Our results reveal an important role for proteasome-mediated proteostasis in adipocytes and indicate that Nfe2l1 is linked to metabolic health in humans and preclinical mouse models. Promoting proteostasis in adipocytes may thus alleviate inflammation in obesity, potentially averting adverse cardiometabolic outcomes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=191 SRC="FIGDIR/small/604614v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@145e32borg.highwire.dtl.DTLVardef@1454df1org.highwire.dtl.DTLVardef@1002383org.highwire.dtl.DTLVardef@1b7319_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2024

Hepatic Nrf1 (Nfe2l1) promotes VLDL dependent liver defense against sepsis

Sepsis causes mortality by triggering organ damage. Interest has emerged in stimulating disease tolerance to reduce organ damage. Liver plays a role in disease tolerance by mediating defensive adaptations, but sepsis-induced liver damage limit these effects. Here, we investigated whether stress defending transcription factors nuclear factor erythroid 2 related factor-1 (Nrf1) and -2 (Nrf2) in hepatocytes protect against sepsis. Using mice, we evaluated responses by hepatic Nrf1 and Nrf2 during sepsis triggered by lipopolysaccharide or Escherichia coli. We also genetically altered hepatic Nrf1 and Nrf2 activity to determine the protective role of these factors in sepsis. Our results show hepatic Nrf1 and Nrf2 activity is reduced in severe sepsis and hepatic Nrf1, but not Nrf2, deficiency predisposes for hypothermia and mortality. In contrast, enhancing hepatic Nrf1 activity protects against hypothermia and improves survival. Moreover, in sepsis hepatic Nrf1 deficiency reduces VLDL secretion whereas enhancing hepatic Nrf1 increases VLDL secretion, and inhibiting VLDL secretion with lomitapide obstructs protective actions of hepatic Nrf1. Gene expression profiles suggest Nrf1 promotes this effect by inducing stress defenses. Hence, we show mortality in sepsis may result from impaired stress defense and that hepatic Nrf1 improves disease tolerance during sepsis by promoting VLDL dependent liver defense.

physiology↗

bioRxiv2024

Sterol O-acyltransferase (SOAT/ACAT) activity is required to form cholesterol crystals in hepatocyte lipid droplets

ObjectiveExcess unesterified (free) cholesterol can induce formation of cholesterol crystals in hepatocyte lipid droplets. Presence of such crystal distinguishes metabolic dysfunction associated steatohepatitis (MASH) from simple steatosis and may underlie its pathogenesis by causing cell damage that triggers liver inflammation. The mechanism linking cholesterol excess to its crystallization in lipid droplets is unclear. As cholesteryl esters localize to and accumulate in lipid droplets much more readily than free cholesterol, we investigated whether cholesterol esterification by sterol O-acyltransferase (SOAT), also known as acyl co-A cholesterol acyltransferase (ACAT) is required for hepatocyte lipid droplet crystal formation. MethodCholesterol crystals were measured in cholesterol loaded Hep3B hepatocytes, RAW264.7 macrophages and mouse liver using polarizing light microscopy. We examined the effect of blocking SOAT activity on crystal formation and compared these results to cholesterol metabolism and the progression to intracellular crystal deposits. ResultsCholesterol loading of Hep3B cells caused robust levels of lipid droplet localized crystal formation in a dose- and time-dependent manner. Co-treatment with SOAT inhibitors and genetic ablation of SOAT1 blocked crystal formation. SOAT inhibitor also blocked crystal formation in low density lipoprotein (LDL) treated Hep3B cells, acetylated LDL treated RAW 264.7 macrophages, and in the liver of mice genetically predisposed to hepatic cholesterol overload and in mice fed a cholesterol enriched, MASH-promoting diet for 24 weeks. ConclusionSOAT1-mediated esterification may underlie cholesterol crystals associated with MASH by concentrating it in lipid droplets. These findings imply that inhibiting hepatocyte SOAT1 may alleviate cholesterol associated MASH. Moreover, that a lipid droplet localized cholesteryl ester hydrolase may be required for cholesterol crystal formation or, instead, that the crystals are composed of cholesteryl ester. Funding SourcesGrants supporting this research were awarded to SBW from the Natural Sciences and Engineering Research Council of Canada (NSERC). SBW was supported by a National New Investigator Award and McDonald Scholarship from the Heart and Stroke Foundation of Canada. UN and MA were supported by a James Regan Cardiology Research scholarship from University of Saskatchewans College of Medicine.

molecular biology↗