Journal of Lipid Research最新文献

In an interplay with parenchymal cells of metabolically active organs, such as heart and adipose tissues, vascular endothelial cells are important for the regulation of nutrient uptake and organ-specific energy metabolism. Based on high expression of the scavenger receptor class B type I (SR-B1) in capillary endothelial cells of white adipose tissue and brown adipose tissue (BAT), we proposed a functional role for this receptor in lipid handling and adaptive thermogenesis. To address this hypothesis, we generated mice with an endothelial-specific KO of SR-B1 and performed metabolic turnover and indirect calorimetry studies in response to environmental cues, such as cold exposure and high-fat diet feeding. Compared with control littermates, endothelial-specific SR-B1 KO mice had substantially lower SR-B1 mRNA and protein levels in heart, skeletal muscle, BAT, and white adipose tissue but not in liver, indicating that SR-B1 is primarily expressed by endothelial cells in peripheral organs. We did not detect major differences in gene expression of thermogenic and lipid-handling genes, energy expenditure assessed by indirect calorimetry, or clearance of metabolic tracers for glucose and triglycerides between endothelial SR-B1 KO mice and controls under basal conditions, thermogenic activation, or high-fat diet feeding. However, consistent with the importance of SR-B1 expression by hepatocytes for HDL metabolism, mice lacking endothelial SR-B1 had lower selective cholesterol uptake in the heart and BAT compared with control littermates. We conclude that endothelial SR-B1 is not essential for adaptive thermogenesis and handling of triglyceride-rich lipoproteins, but it is involved in regulating cholesterol homeostasis in the heart and BAT.

Alcoholic liver disease (ALD) encompasses a spectrum of disorders, with advanced ALD-characterized by liver fibrosis-representing a severe stage with high mortality. The National Institute on Alcohol Abuse and Alcoholism ALD mouse model, a classical approach to studying ALD by delivering alcohol through the Lieber-DeCarli (LD) diet, typically does not progress to advanced ALD. We previously determined that ferroptosis causes hepatocellular injury in this model. Here, we speculate that the enrichment of MUFAs and vitamin E, which inhibit ferroptosis, and the lack of the proferroptotic nutrient iron in the LD diet may limit the progression of ALD by inhibiting ferroptosis. To test this hypothesis, we modified the LD diet to generate a proferroptotic LD (PFLD) diet by depleting vitamin E, increasing dietary levels of iron, and replacing MUFAs with PUFAs that drive ferroptosis. Upon feeding alcohol through the PFLD diet, ∼30% of the mice developed liver fibrosis and macrosteatosis, hallmarks of advanced ALD. These pathological changes were associated with exacerbated ferroptosis, possibly driven by overaccumulation of PUFA-containing triglycerides. Our findings underscore the critical role of dietary lipid composition in determining ALD severity, and demonstrate that feeding alcohol through the PFLD diet may serve as a mouse model for advanced ALD.

Alzheimer's disease (AD) presents a significant challenge owing to its widespread prevalence and complex neuropathogenesis, affecting millions worldwide. Current therapeutic strategies that predominantly target amyloid-beta accumulation are insufficient, particularly for ApoE4 carriers. Alterations in lipid composition are well documented in AD, characterized by reductions in phospholipids and sulfatides, along with increases in cholesterol, cholesteryl esters, and triglycerides (TGs). Microglia, the brain's resident immune cells, link dysfunctional lipid processing to AD neuropathogenesis. For example, genetic studies have pointed to microglial lipid and lipoprotein processing gene variants as some of the strongest risk factors for AD. In addition, microglial dysfunction, characterized by lipid droplet accumulation, increased cholesterol and TG levels, and altered lipid transport, may exacerbate the pathological hallmarks of AD, such as amyloid-beta and tau accumulation. Conversely, emerging studies have shown that strategies aimed at inhibiting lipid droplet accumulation in microglia, reducing TG synthesis, and promoting the activity of lipoprotein receptors expressed by microglia can improve cell functions and markers of AD pathology. This review dissects the interplay between microglial lipid metabolism and AD, highlighting the significance of lipid transport and trafficking within the CNS. Given the intrinsic link between microglial metabolism and AD progression, emerging and potential therapeutic strategies aimed at restoring lipid handling and improving microglial function are explored. This review provides a comprehensive examination of the emerging literature, detailing the current state of knowledge on microglial lipid metabolism, its genetic underpinnings, and the potential for novel interventions targeting these mechanisms to ameliorate AD pathology.

Carboxylesterases (CESs) are essential for metabolizing compounds with ester, thioester, and amide bonds. While the roles of CES1 and CES2 in lipid metabolism have been well established, little is known about the role of CES3 in lipid metabolism or metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we report the localization and nutritional regulation of CES3 and its role in MASLD development in mice. CES3 is expressed exclusively in the liver and localizes to the ER. Hepatic CES3 is reduced in patients with metabolic dysfunction-associated steatohepatitis and mice fed a Western diet. Unexpectedly, loss of CES3 alleviates Western diet-induced MASLD, whereas liver-specific overexpression of human CES3 worsens Western diet-induced MASLD. Mechanistically, loss of CES3 reduces de novo lipogenesis and promotes the secretion of VLDL-triglycerides. Thus, the current study has identified a novel role of CES3 in hepatic lipid metabolism and MASLD.

The ABCG5/ABCG8 (G5G8) sterol transporter opposes the accumulation of dietary xenosterols but is also the primary mediator of biliary cholesterol secretion. In humans and in mouse models of disrupted biliary cholesterol secretion, fecal neutral sterols (FNSs) remain constant, indicating the presence of an alternate pathway for cholesterol excretion. Transintestinal cholesterol elimination or excretion (TICE) is thought to compensate for biliary disruptions and G5G8 insufficiency. We sought to measure the compensatory increase in intestinal cholesterol secretion and provide mechanistic insight for how TICE maintains sterol balance in the absence of hepatic G5G8. Differences were not observed in FNSs between control, acute, and chronic liver-specific G5G8-deficient mice (G5G8^LKO). Cholesterol content did not differ at any point along the intestinal tract between genotypes. We also observed no change in the expression of apical or basolateral sterol transporters in the proximal small intestine. We then measured biliary and intestinal cholesterol secretion rates using cholesterol-free and cholesterol-enriched bile acid micelles as acceptors. While biliary cholesterol secretion was reduced, the intrinsic rate of intestinal cholesterol secretion did not differ between genotypes. G5G8^LKO and whole-body G5G8-deficient mice were challenged with a cholesterol-containing diet. While control mice upregulate FNS excretion, G5G8-independent mechanisms fail to maintain fecal sterol excretion and oppose the accumulation of cholesterol in liver and plasma. These studies indicate that while G5G8-independent mechanisms can mediate cholesterol excretion, TICE is not upregulated in response to a loss of hepatic G5G8 and is unable to compensate for hepatic or whole-body G5G8 deficiency in response to dietary cholesterol in mice.

Young females have higher circulating docosahexaenoic acid (DHA) levels than males, though the metabolic basis remains incompletely understood. Building on previous findings that demonstrate higher hepatic synthesis of the DHA precursor, docosapentaenoic acid (DPAn-3), in males, this study extends the investigation to n-3 PUFA turnover in extrahepatic tissues of male and female C57BL/6N mice using compound-specific isotope analysis (CSIA). Animals were fed a 12-week diet enriched in either α-linolenic acid (ALA), eicosapentaenoic acid (EPA), or DHA, starting with a 4-week phase containing low carbon-13 (δ¹³C)-n-3 PUFA, followed by an 8-week phase with high δ¹³C-n-3 PUFA (n = 4 per diet, time point, sex). Heart, perirenal adipose tissue (PRAT), brain, and red blood cells (RBCs) were collected at baseline and at seven time points (1-56 days) post-diet switch, with δ¹³C-n-3 PUFA values modeled by one-phase exponential decay. Compared to males, females exhibited slower turnover of ALA (48%-61% slower) and DPAn-3 (26%-73% slower) from dietary ALA or EPA in the heart, PRAT, and RBCs, resulting from longer half-lives and/or lower DPAn-3 concentrations. Conversely, females showed 26%-28% faster heart DHA turnover from dietary ALA or EPA, despite similar half-lives between sexes. Notably, sex-specific differences in DHA turnover were present only in the heart, whereas DPAn-3 turnover varied across multiple tissues, suggesting a heart-specific mechanism that enhances DHA metabolism in females under low DHA intake. Further research is needed to investigate the physiological significance of these metabolic differences and their potential health implications.

Neuronal growth regulator 1 (NEGR1) has been identified as a critical risk factor for major depressive disorders in humans. Although NEGR1 is predominantly expressed in the brain, its deletion in mice (Negr1^-/-) results in abnormalities in peripheral tissues, suggesting a role beyond the nervous system, particularly in intracellular lipid trafficking. However, the role of NEGR1 in testosterone production has not yet been elucidated. Here, we demonstrate that Negr1^-/- mice exhibit significantly reduced serum and testicular testosterone levels, accompanied by diminished male reproductive behaviors. The expression of key testosterone-synthesizing enzymes was downregulated in Leydig cells, and histological analysis revealed disorganized testicular and epididymal structures with lipid droplet accumulation in testicular cells. Additionally, Negr1^-/- mice displayed a significant increase in abnormal sperm morphology. Notably, testosterone supplementation alleviated their impaired sexual behaviors and mitigated anxiety- and depression-like phenotypes. These findings highlight a crucial role for NEGR1 in testicular function, particularly in testosterone production and spermatogenesis, underscoring the intricate link between hormonal balance and mental health.

Atherosclerosis begins with the subendothelial retention of LDLs from the circulation. While LDL transcytosis across the endothelium is mediated by scavenger receptor class B type I and activin-like kinase receptor 1 and is usually independent of LDL receptor, the intracellular mechanisms and route of LDL transcytosis remain unclear. Using total internal reflection fluorescence microscopy in LDL receptor-depleted human coronary artery endothelial cells, we found that LDL transcytosis can proceed both directly and indirectly from an intracellular compartment. During LDL transcytosis, LDL was observed to colocalize with the Golgi apparatus over time, specifically with the trans-Golgi network marker TGN46. Systematic examination of endothelial Rab proteins known to regulate Golgi traffic identified Rabs 6a and 10 to be required for LDL transcytosis. Depletion of Rab10 or Rab6a significantly inhibited LDL transcytosis but had no effect on albumin transcytosis. Expression and localization of scavenger receptor class B type I and activin-like kinase receptor 1 were also unimpaired. Conversely, overexpression of Rab10 increased LDL transcytosis. Finally, depletion of Rab10 increased colocalization of LDL with the trans-Golgi network and led to expansion of the Golgi, indicative of impaired exocytosis from the Golgi. However, colocalization of Rab10 with LDL did not increase over time, and Rab10 did not accumulate at the base of the cell, suggesting its role is specifically related to LDL exit from the Golgi rather than direct transport. In summary, during LDL transcytosis, internalized LDL is transported to the Golgi, which serves as a reservoir of LDL that can undergo exocytosis. Our results identify specific Rab proteins as critical regulators of this process.

Hepatic steatosis presents a rising challenge in liver transplantation (LT), yet the precise underlying players remain incompletely understood. As steatosis reflects the accumulation of several types of lipids, including cholesterol, which has emerged as a key player in metabolic-dysfunction associated fatty liver disease, we aimed to characterize the content of lipids and the expression of cholesterol metabolic genes in liver biopsies before (pre-LT) and after LT (post-LT), with the ultimate goal of identifying factors that may impact graft loss and the overall outcomes of LT. Lipid content and cholesterol-related genes in pre- and post-LT graft biopsies, clinical outcome, and survival within the first year after LT were analyzed in 174 patients. Unlike free fatty acids (FFA) and triglycerides, total and free cholesterol (FC) levels are maintained in pre- and post-LT samples. Increased FC and FFA levels in pre-LT samples were associated with early allograft dysfunction (EAD). The increase in the expression of cholesterol regulatory genes SREBF2 and HMGCR in pre-LT samples was identified as a potential risk factor of death after LT, particularly with SREBF2, whose expression is associated with EAD and graft loss (GL). Collectively, these data link the expression of genes involved in the synthesis of cholesterol to LT-related mortality. These findings may translate to an increased application of marginal steatotic grafts in LT, thereby promoting a safe outcome.

We recently found that plasminogen receptors regulate the plasma membrane binding and uptake of Lp(a) via macropinocytosis. In this study, we sought to further define lipoprotein(a) [Lp(a)] macropinocytosis, discovering an unexpected role for antidepressants and serotonin in the regulation of this process. We found that the tricyclic antidepressant imipramine enhanced Lp(a) uptake, in contradiction of its published role as a macropinocytosis inhibitor. Extending these experiments to the commonly used serotonin uptake inhibitors (SSRIs) citalopram, sertraline, fluoxetine, and paroxetine, we found that citalopram and paroxetine stimulated Lp(a) uptake. Imipramine and citalopram enhanced cell surface binding of Lp(a) to increase uptake by macropinocytosis. Consistent with imipramine and citalopram boosting extracellular serotonin levels, serotonin itself also enhanced Lp(a) surface binding and uptake. In contrast to Lp(a), imipramine and citalopram had no effect on low-density lipoprotein (LDL) uptake. Imipramine and serotonin increased expression of the plasminogen receptor with a C-terminal lysine (PlgRKT), a receptor known to enhance cell surface binding of Lp(a), likely accounting for their effects on Lp(a) uptake. Finally, imipramine and citalopram increased Lp(a) delivery into Rab11 recycling endosomes but not degradative pathways in the cell. These findings indicate SSRIs such as citalopram and paroxetine may have utility as a potential Lp(a)-lowering therapeutic in people suffering from depression who often have elevated Lp(a) levels and an increased risk of cardiovascular disease.