Background Acute kidney injury (AKI) frequently causes remote organ injury including hepatic steatosis, yet whether lipid accumulation reflects increased synthesis or impaired clearance has not been resolved. Methods We used a murine ischemia-reperfusion AKI model. Unbiased liver proteomics was performed at 24 hours after reperfusion, and dysregulated pathways were identified by Gene Set Enrichment Analysis. Results were validated by Western blotting, qPCR, and immunohistochemistry. These findings were complemented by retrospective analysis of two ICU databases (MIMIC-IV and eICU-CRD). Results AKI significantly increased serum ALT and AST and induced hepatic lipid accumulation. Proteomic analysis revealed that key lipogenic enzymes (Scd1, Fasn, Acly, Acaca) were uniformly suppressed rather than upregulated. Proteins essential for VLDL assembly (ApoB, MTTP, ApoE) were significantly downregulated. Plasma triglycerides were decreased while liver triglycerides were increased, consistent with impaired hepatic lipid export. As in renal tubular cells, AKI also disrupted ER protein folding homeostasis in the liver, triggering ER stress. This was evidenced by upregulated levels of the ER chaperone GRP78, increased XBP1 splicing indicative of UPR activation, and elevated expression of the ER stress-induced pro-apoptotic transcription factor CHOP, suggesting that prolonged ER stress may also promote hepatocyte cell death. TLR4/MyD88 signaling was activated, yet inflammatory cytokines were paradoxically reduced, accompanied by Kupffer cell depletion (decreased F4/80) and monocyte infiltration (increased CD68). In 6,996 propensity-matched ICU patients (MIMIC-IV), AKI independently increased the risk of clinically significant liver injury 4-fold (adjusted OR = 4.41). Analysis of 22,727 patients across 208 hospitals (eICU-CRD) identified a lipid dissociation pattern: elevated triglycerides alongside decreased total cholesterol, HDL, and LDL, with dose-dependent scaling across KDIGO stages. Conclusions These data support ER stress-mediated impairment of VLDL export as a primary driver of AKI-induced hepatic steatosis. Clinical validation across two independent ICU databases identifies a dual metabolic insult: enhanced peripheral lipid delivery compounds impaired hepatic export, amplifying hepatic lipid retention. ER stress and lipid export machinery represent potential therapeutic targets for AKI-associated liver injury.

It has been confirmed that cholesterol-lowering therapy, particularly the reduction of low-density lipoprotein cholesterol (LDL-C) levels, represents the most effective measure for decreasing the incidence of atherosclerotic cardiovascular disease and related cardiovascular events. Previous studies have shown that active reduction of cholesterol levels significantly increases the goal attainment rate of LDL-C and improves clinical outcomes. Although many cholesterol-lowering medications are currently available in clinical practice and the cholesterol lowering treatment status has improved, the real-world cholesterol management in China, especially the goal attainment rate of LDL-C, is not satisfactory. This issue is closely related to the selection of initial cholesterol-lowering treatment strategies. Furthermore, clinical research has demonstrated that the safety and adherence of cholesterol-lowering therapy are also critical factors influencing treatment effectiveness. In response, the National Cardiovascular Disease Expert Committee Cardiovascular Metabolic Medicine Professional Committee has organized domestic experts to systematically and comprehensively review methods and scientific choices for initiating cholesterol-lowering therapy in the Chinese population and developed a Chinese expert consensus on the selection of initial cholesterol-lowering strategies based on current evidence. It aims to propose optimized initial treatment regimens tailored to individual characteristics, thereby further improving the prevention and management of dyslipidemia in Chinese population.

Hepatic ischemia-reperfusion injury (IRI) is a complex event influenced by interconnected immune and metabolic processes. Steatotic livers are especially sensitive to IRI, but the crosstalk between innate inflammatory responses and lipid metabolic dysregulation in this context is not well understood. Using transcriptomic profiling in a murine high-fat diet (HFD) model, we assessed immune and metabolic responses to hepatic IRI and examined the effects of N-acetylcysteine (NAC). In steatotic livers, IRI induced the upregulation of inflammatory mediators, including TLR/NF-κB-associated genes (Tlr2, Tlr4, Irf1) and neutrophil-associated genes (S100a8, S100a9, Lcn2), accompanied by the downregulation of lipid and cholesterol metabolism-related genes, including Cyp7a1, Cyp8b1, Cyp27a1, and Hmgcr. NAC supplementation attenuated inflammatory gene expression and restored key lipid biosynthetic regulators. We then performed targeted lipidomic analysis to determine whether NAC-mediated transcriptional changes were reflected at the lipid level and observed a significant increase in total phosphatidylcholine and sphingomyelin in steatotic livers following IRI. Finally, to assess the contribution of innate immune cells to hepatic IRI, we quantified neutrophils and macrophages in HFD+NAC IRI and HFD IRI livers. We found that NAC supplementation reduced hepatic neutrophil accumulation and markedly decreased LCN2 expression following IRI.

A man in his late 60s with a history of arterial hypertension, dyslipidaemia and a cerebrovascular accident 20 years ago presented to the emergency department with sudden-onset blurred vision in his right eye, accompanied by pain, dizziness, sweating and high blood pressure (160/110 mmHg). Ophthalmic examination revealed a decreased visual acuity in the right eye (less than 6/60), with best corrected visual acuity of 6/7.5. Fundoscopy showed retinal cholesterol emboli and ischaemic changes. Carotid duplex ultrasound indicated possible stenosis of the internal carotid artery. The patient was started on antiplatelet therapy with acetylsalicylic acid and 24-hour cardiac telemetry monitoring. A brain MRI performed 2 days later showed acute ischaemic infarcts in the right frontal and periventricular regions. Intracranial and cervical magnetic resonance angiography confirmed internal carotid artery occlusion with no flow in the intracranial portion.

Cellular senescence plays a crucial role in brain aging and the decline of cognitive abilities. Although senolytic treatments, particularly the combination of dasatinib and quercetin (D+Q), show potential for improving cognition, the specific mechanisms involved are not well understood. In this study, we present strong evidence that senolytics enhance cognitive function by modulating cholesterol biosynthesis in astrocytes. Using a murine model of accelerated aging (via D-galactose exposure), we show that administering D+Q results in significant improvements in cognitive performance and a decrease in cellular senescence. A comprehensive multi-omics analysis subsequently demonstrated that senolytics are especially effective at downregulating cholesterol biosynthesis in the hippocampus. Notably, this effect was localized to astrocytes, where senolytics significantly reduced intracellular lipid accumulation and subsequent neuroinflammation. Critically, pharmacological activation of cholesterol synthesis and genetic overexpression of Hsd17b7, a key enzyme in the cholesterol synthesis pathway, in astrocytes reversed the anti-senescence benefits of senolytics in vitro, establishing a causal link between cholesterol pathway inhibition and the therapeutic effects. Overall, our work identifies the suppression of astrocytic cholesterol biosynthesis as a fundamental mechanism of senolytic action, repositioning these compounds as modulators of brain lipid metabolism and highlighting a promising therapeutic axis for combating age-related cognitive decline.

The objective of this study was to investigate the effects of chromium yeast (Cr yeast) on lipid metabolism, antioxidant status, and gene expression related to meat development in broilers under high stocking density (HSD). A total of 480 22-day-old male Arbor Acre (AA) broilers with similar initial weight were randomly allocated to 6 groups, with 6 replicates per group. The groups consisted of a normal stocking density (14 broilers/m2, NSD) group fed a corn-soybean meal basal diet; high stocking density group (20 broilers/m2 , HSD) fed a basal diet; and four HSD groups fed basal diets supplemented with 200, 400, 800, or 1600 μg Cr/kg from Cr yeast. The experiment lasted from day 23 to 42. The results showed that compared to the NSD group, HSD elevated serum levels of insulin (INS), insulin-like growth factor-I (IGF-I), triglycerides, and high-density lipoprotein cholesterol (HDLC), increased hepatic activities of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), and decreased serum total cholesterol (TC) along with hepatic and breast muscle activities of hormone-sensitive lipase (HSL) and lipoprotein lipase (LPL) (P < 0.05). Compared with the HSD group, supplementation with 400 μg/kg Cr enhanced lipid breakdown in HSD-exposed broilers by elevating serum leptin content and increasing hepatic HSL and LPL activities, while simultaneously reducing serum INS, IGF-1, and TC levels, along with hepatic FAS activity (P < 0.05). HSD upregulated heat shock protein 70 (HSP70) mRNA expression while downregulated myostatin (MSTN) mRNA expression in breast muscle (P < 0.05), compared to the NSD group. Cr supplementation at 200, 800, and 1600 µg/kg significantly increased nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA expression in breast muscle (P = 0.008) without affecting other antioxidant genes expression. Furthermore, supplementation with 800 and 1600 µg/kg Cr from Cr yeast elevated mRNA levels of both myogenic factor 6 (MyoF6) and MSTN, while downregulated fatty acid-binding protein 4 (FABP4) mRNA expression in breast muscle (P < 0.05). In summary, dietary Cr yeast alleviated HSD-induced metabolic stress by enhancing lipid breakdown and modulating the expression of key genes involved in muscle development and lipid metabolism, thereby supporting metabolic homeostasis and muscle function under HSD.

Metabolic dysfunction-associated steatohepatitis (MASH) increases liver-related mortality, and new therapies targeting its underlying mechanisms are warranted. We examined whether two lipid-droplet proteins, CIDEB and CGI-58, exert opposing control over MASH by altering cholesterol in liver lipid droplets. Using antisense oligonucleotides, we silenced CIDEB or CGI-58 in the livers of C57BL/6J mice fed a choline-deficient, L-amino acid-defined high-fat diet. CIDEB silencing decreased both triglyceride and cholesterol levels in liver lipid droplets and lowered plasma transaminases and the number of crown-like structures. These protective effects were abrogated by cholesterol supplementation. Conversely, CGI-58 knockdown raised triglyceride and cholesterol levels and exacerbated MASH; bempedoic acid, a cholesterol-synthesis inhibitor, reversed these changes. Dual CIDEB/CGI-58 silencing confirmed that CGI-58 loss abrogated the protective effects of CIDEB knockdown. Our data establish liver lipid-droplet cholesterol as a critical determinant in MASH mediated by CIDEB and CGI-58 and demonstrate that CIDEB knockdown confers protection by enhancing CGI-58-dependent lipolysis.

Cholesterol homeostasis is fundamental to cellular function, and its disruption underlies a wide range of human diseases. However, the contribution of cholesterol biosynthesis to auditory physiology remains poorly understood. HSD17B7 (17β-Hydroxysteroid dehydrogenase type 7) catalyzes the conversion of zymosterone to zymosterol, a key step in the post-lanosterol cholesterol biosynthetic pathway. Here, we found that Hsd17b7 is highly enriched in sensory hair cells of zebrafish and mice. The deficiency of Hsd17b7 reduced intracellular cholesterol levels in HEI-OC1 cells and zebrafish hair cells, thereby compromising MET and acoustic startle responses. A heterozygous nonsense variant (c.544G>T; p.E182*) in HSD17B7 was identified in an individual with bilateral profound hearing loss. mRNA of c.544G>T HSD17B7 failed to rescue the impaired MET and acoustic startle response of hsd17b7 mutants. Mechanistically, the mutation decreases mRNA abundance and significantly reduces protein. Moreover, expression of the p.E182* mutation disrupted the interaction between HSD17B7 and the ER retention receptor RER1, leading to aberrant subcellular localization and altered cholesterol distribution, thereby exacerbating HC dysfunction. Together, our findings suggest a conserved and essential role for HSD17B7-mediated cholesterol biosynthesis in sensory hair cell function and identify HSD17B7 as a candidate gene for sensorineural hearing loss.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disorder and can progress to steatohepatitis and fibrosis; although approved pharmacotherapies for metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis remain limited. Autologous chemically induced liver progenitor (CLiP) cells, generated from mature hepatocytes without genetic modification, have shown therapeutic promise in rodents, but their efficacy has not been tested in large animals. Six female Clawn miniature pigs (15-42 kg) were fed a high-fat, high-cholesterol diet to induce MASLD with biopsy-proven fibrosis (Brunt stage ≥1). Animals were assigned to CLiP transplantation (n = 3) or saline control (n = 3). Autologous CLiPs (5 × 107) were generated from laparoscopically resected liver wedges, expanded ex vivo, and infused intraportally. Safety was assessed by monitoring, liver function tests, and lipid profiles. Efficacy was evaluated 1 month later by blinded histology and immunohistochemistry. CLiP transplantation was feasible and well tolerated. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) showed minimal changes in both groups, but total cholesterol and triglycerides decreased in treated pigs and increased in controls. Histologically, two of three CLiP-treated livers regressed from Brunt stage 1 to 0, with resolution of steatosis and reduced stellate cell activation, whereas controls showed no regression. These findings support CLiP therapy as a regenerative option for MASLD.

Climate change and rising ambient temperatures increasingly challenge sheep production systems in arid and semi-arid regions, particularly during the summer breeding season. This study evaluated the effects of heat stress and direct solar exposure on physiological responses, metabolic profile, and reproductive performance of Barbarine ewes, a fat-tailed breed adapted to harsh environments. A total of 112 non-lactating multiparous ewes were allocated to two groups during summer mating: an indoor group protected from solar radiation (IDGp; n = 58) and an outdoor group exposed to direct sunlight (ODGp; n = 54). Both groups experienced severe to extreme heat stress for more than 65% of the experimental period. Sun exposure significantly increased rectal temperature (+0.2 to +0.6°C), respiratory rate (up to 130 vs 61 breaths/min), and heart rate (up to 95 vs 87 beats/min) in outdoor ewes (ODGp) compared to indoor ewes (IDGp), indicating a higher physiological heat load in sun-exposed animals. The temperature-humidity index (THI) remained comparable between groups (≈24.7), suggesting comparable THI values. Metabolic responses were characterized by increased plasma concentrations of triglycerides (+36%), total proteins (+7.5%), urea (+13%), creatinine (+34%), and potassium (+5%), along with a decrease in cholesterol levels (-15%) in ODGp compared to IDGp. Despite these physiological and metabolic adjustments, body condition score and live weight were maintained in both groups. Reproductive performance was not affected by solar exposure, with estrus occurrence exceeding 94%, an ovulation rate of 1.17, and no significant differences in fertility (79.3% vs 77.8%), prolificacy, or fecundity between groups. These findings indicate that, although direct solar radiation increases physiological strain, it does not impair reproductive function under comparable ambient thermal conditions. Barbarine ewes thus exhibit strong functional resilience to heat stress, highlighting their suitability for extensive production systems in hot and dry environments.