lnc-HC ameliorates steatosis by promoting miR-130b-3p biogenesis and the assembly of an RNA-induced silencing complex.

Hepatic lipid deposition is the main cause of non-alcoholic fatty liver disease (NAFLD). Our previous study identified that lnc-HC prevents NAFLD by increasing the expression of miR-130b-3p. In the present study, we show that lnc-HC, an lncRNA derived from hepatocytes, positively controls miR-130b-3p maturation at multiple levels and contributes to its action by enhancing the assembly of an RNA-induced silencing complex (RISC). lnc-HC negatively regulates the downstream target genes of miR-130b-3p, including peroxisome proliferator-activated receptor gamma (PPARγ) and acyl-CoA synthetase long-chain family member 1 and 4 (Acsl1 and Acsl4, respectively), thus suppressing hepatic lipid droplet accumulation. Mechanistically, lnc-HC enhanced the promoter activity of miR-130b-3p by positively regulating the expression of transcription factors MAF bZIP transcription factor B (Mafb) and Jun proto-oncogene (Jun). Then, lnc-HC contributed the processing step of primary (pri-) miR-130b and strengthened the interaction between Drosha enzyme and the 5'-flanking sequence of pri-miR-130b to produce more precursor transcripts. Through direct binding with the chaperone heat shock protein 90 alpha family class A member 1 (HSP90AA1), lnc-HC contributed to RISC assembly, which was composed of HSP90AA1, argonaute RISC catalytic component 2 (AGO2) and miR-130b-3p. In a high-fat, high-cholesterol-induced hepatic lipid disorder E3 model, we confirmed that the hepatic expression of lnc-HC/miR-130b-3p negatively correlated with that of the target genes and was closely associated with liver triglycerides concentration. These findings provide a deeper understanding of the regulatory roles of lnc-HC in hepatic lipid metabolism and NAFLD development.

Endotoxin Tolerance Acquisition and Altered Hepatic Fatty Acid Profile in Aged Mice.

(1) Background: Aging is linked to an altered immune response and metabolism. Inflammatory conditions, such as sepsis, COVID-19, and steatohepatitis are more prevalent in the elderly and steatosis is linked both to severe COVID-19 and sepsis. We hypothesized that aging is linked to a loss of endotoxin tolerance, which normally protects the host from excessive inflammation, and that this is accompanied by elevated levels of hepatic lipids. (2) Methods: An in vivo lipopolysaccharide (LPS) tolerance model in young and old mice was used and the cytokine serum levels were measured by ELISA. Cytokine and toll-like receptor gene expression was determined by qPCR in the lungs and the liver; hepatic fatty acid composition was assessed by GC-MS. (3) Results: The old mice showed a distinct potential for endotoxin tolerance as suggested by the serum cytokine levels and gene expression in the lung tissue. Endotoxin tolerance was less pronounced in the livers of the aged mice. However, the fatty acid composition strongly differed in the liver tissues of the young and old mice with a distinct change in the ratio of C18 to C16 fatty acids. (4) Conclusions: Endotoxin tolerance is maintained in advanced age, but changes in the metabolic tissue homeostasis may lead to an altered immune response in old individuals.

Effects of feeding broiler breeder hens a coextruded full-fat flaxseed and pulses mixture without or with multienzyme supplement.

The effects of coextruded full-fat flaxseed and pulses (FFF; 1:1 wt/wt) mixture on n-3 polyunsaturated fatty acids (PUFA) enrichment in egg yolk, hepatic attributes, apparent retention (AR) of components, and ceca metabolites were evaluated in broiler breeder hens. The diets were as follows: 1) corn-soybean control, 2) control diet plus 18% FFF (FFF-), and 3) FFF plus enzyme supplement (FFF+) containing galactanase, protease, mannanase, glucanase, xylanase, amylase, and cellulase activities. Twenty-six-week-old Cobb 500 broiler breeder hens were allocated to 30 identical cages (2 hens/cage) and given 1-week adaptation period. The 3 diets were assigned to 10 replicate cages based on postadaptation BW and fed based on breeder curve for 30 D. Excreta samples were collected from day 24 to 27 for determination of AR of components, and eggs were collected from day 28 to 30 for yolk polyunsaturated fatty acids analyses. On day 30, birds were weighed, killed via cervical dislocation, liver weighed, and stored for fat analyses. Ceca digesta samples were taken for concentration of short-chain fatty acids. Liver and yolk weights as well as total yolk FA were not influenced by diets (P > 0.05). Control birds had lower yolk concentration of α-linolenic acid than birds fed either FFF- or FFF+ (P < 0.01) corresponding to 7.5, 36.8, and 37.3 mg/g for the control, FFF-, and FFF+, respectively. Control birds also exhibited lower yolk concentration of docosahexaenoic acid (P < 0.01). Control birds had higher hepatic concentration of crude fat and apparent retention of dry matter and crude protein compared with either the FFF- or FFF+ birds (P < 0.05). Birds fed FFF- diet had lower ceca digesta concentration of lactic acid than control and FFF+ (P < 0.05) birds. Results showed broiler breeder hens enriched egg yolk with n-3 polyunsaturated fatty acids without effects on the liver while the supplemental enzyme did not improve the utilization of FFF.

Dietary grape seed proanthocyanidin extract regulates metabolic disturbance in rat liver exposed to lead associated with PPARα signaling pathway.

Lead, a pervasive environmental hazard worldwide, causes a wide range of physiological and biochemical destruction, including metabolic dysfunction. Grape seed proanthocyanidin extract (GSPE) is a natural production with potential metabolic regulation in liver. This study was performed to investigate the protective role of GSPE against lead-induced metabolic dysfunction in liver and elucidate the potential molecular mechanism of this event. Wistar rats received GSPE (200 mg/kg) daily with or without lead acetate (PbA, 0.5 g/L) exposure for 56 d. According to biochemical and histopathologic analysis, GSPE attenuated lead-induced metabolic dysfunction, oxidative stress, and liver dysfunction. Liver gene expression profiling was assessed by RNA sequencing and validated by qRT-PCR. Expression of some genes in peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway was significantly suppressed in PbA group and revived in PbA + GSPE group, which was manifested by Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis and validated by western blot analysis. This study supports that dietary GSPE ameliorates lead-induced fatty acids metabolic disturbance in rat liver associated with PPARα signaling pathway, and suggests that dietary GSPE may be a protector against lead-induced metabolic dysfunction and liver injury, providing a novel therapy to protect liver against lead exposure.