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The roles of dietary cholesterol in fish physiology are currently contradictory. The issue reflects the limited studies on the metabolic consequences of cholesterol intake in fish. The present study investigated the metabolic responses to high cholesterol intake in Nile tilapia (Oreochromis niloticus), which were fed with four cholesterol-contained diets (0.8, 1.6, 2.4 and 3.2%) and a control diet for eight weeks. All fish-fed cholesterol diets showed increased body weight, but accumulated cholesterol (the peak level was in the 1.6% cholesterol group). Then, we selected 1.6% cholesterol and control diets for further analysis. The high cholesterol diet impaired liver function and reduced mitochondria number in fish. Furthermore, high cholesterol intake triggered protective adaptation via (1) inhibiting endogenous cholesterol synthesis, (2) elevating the expression of genes related to cholesterol esterification and efflux, and (3) promoting chenodeoxycholic acid synthesis and efflux. Accordingly, high cholesterol intake reshaped the fish gut microbiome by increasing the abundance of Lactobacillus spp. and Mycobacterium spp., both of which are involved in cholesterol and/or bile acids catabolism. Moreover, high cholesterol intake inhibited lipid catabolic activities through mitochondrial β-oxidation, and lysosome-mediated lipophagy, and depressed insulin signaling sensitivity. Protein catabolism was elevated as a compulsory response to maintain energy homeostasis. Therefore, although high cholesterol intake promoted growth, it led to metabolic disorders in fish. For the first time, this study provides evidence for the systemic metabolic response to high cholesterol intake in fish. This knowledge contributes to an understanding of the metabolic syndromes caused by high cholesterol intake or deposition in fish.

Hormone-sensitive lipase (HSL) is one of the rate-determining enzymes in the hydrolysis of TAG, playing a crucial role in lipid metabolism. However, the role of HSL-mediated lipolysis in systemic nutrient homoeostasis has not been intensively understood. Therefore, we used CRISPR/Cas9 technique and Hsl inhibitor (HSL-IN-1) to establish hsla-deficient (hsla-/-) and Hsl-inhibited zebrafish models, respectively. As a result, the hsla-/- zebrafish showed retarded growth and reduced oxygen consumption rate, accompanied with higher mRNA expression of the genes related to inflammation and apoptosis in liver and muscle. Furthermore, hsla-/- and HSL-IN-1-treated zebrafish both exhibited severe fat deposition, whereas their expressions of the genes related to lipolysis and fatty acid oxidation were markedly reduced. The TLC results also showed that the dysfunction of Hsl changed the whole-body lipid profile, including increasing the content of TG and decreasing the proportion of phospholipids. In addition, the systemic metabolic pattern was remodelled in hsla-/- and HSL-IN-1-treated zebrafish. The dysfunction of Hsl lowered the glycogen content in liver and muscle and enhanced the utilisation of glucose plus the expressions of glucose transporter and glycolysis genes. Besides, the whole-body protein content had significantly decreased in the hsla-/- and HSL-IN-1-treated zebrafish, accompanied with the lower activation of the mTOR pathway and enhanced protein and amino acid catabolism. Taken together, Hsl plays an essential role in energy homoeostasis, and its dysfunction would cause the disturbance of lipid catabolism but enhanced breakdown of glycogen and protein for energy compensation.

Neutral lipases-mediated lipolysis and acid lipases-moderated lipophagy are two main processes for degradation of lipid droplets (LDs). However, the individual and interactive roles of these metabolic pathways are not well known across vertebrates. This study explored the roles of lipolysis and lipophagy from the aspect of neutral and acid lipases in zebrafish. We established zebrafish strains deficient in either adipose triglyceride lipase (atgl-/-; AKO fish) or lysosomal acid lipase (lal-/-; LKO fish) respectively, and then inhibited lipolysis in the LKO fish and lipophagy in the AKO fish by feeding diets supplemented with the corresponding inhibitors Atglistatin and 3-Methyladenine, respectively. Both the AKO and LKO fish showed reduced growth, swimming activity, and oxygen consumption. The AKO fish did not show phenotypes in adipose tissue, but mainly accumulated triacylglycerol (TAG) in liver, also, they had large LDs in the hepatocytes, and did not stimulate lipophagy as a compensation response but maintained basal lipophagy. The LKO fish reduced total lipid accumulation in the body but had high cholesterol content in liver; also, they accumulated small LDs in the hepatocytes, and showed increased lipolysis, especially Atgl expression, as a compensatory mechanism. Simultaneous inhibition of lipolysis and lipophagy in zebrafish resulted in severe liver damage, with the potential to trigger mitophagy. Overall, our study illustrates that lipolysis and lipophagy perform individual and interactive roles in maintaining homeostasis of TAG and cholesterol metabolism. Furthermore, the interactive roles of lipolysis and lipophagy may be essential in regulating the functions and form of mitochondria.

Long-term feeding of fish with a high-fat diet (HFD) causes excess fat deposition and an impairment of immune function. In the present study, we aimed to determine whether dietary tea polyphenols (TPs) would ameliorate the adverse effects of HFD-feeding in GIFT tilapia. Juvenile GIFT tilapias (5.4 ± 0.9 g) were raised in twelve 200-L tanks (three tanks per diet, 20 fish per tank) and fed a control diet (6% fat, 36% protein), an HFD (12% fat, 36% protein), or an HFD supplemented with 50 mg/kg or 200 mg/kg TP for 8 weeks. The fish were hand-fed 5% of their body weight per day in three feeds, and maintained at 28 ± 1 °C under a 14-h light/10-h dark cycle. The fish in each tank were bulk weighed and counted fortnightly, and the daily feed amount was adjusted accordingly. At the end of the trial, the cumulative survival rate was calculated, and the weight gain and feed conversion ratio were calculated according to the bulk weight of fish in each tank. Tissues were collected from nine fish per diet, their organs were weighed, and biochemical and molecular indices were subsequently measured. HFD-feeding significantly increased lipid deposition, reduced cumulative survival from 96% to 75%, reduced hepatic alkaline phosphate activity (AKP) and serum total antioxidant capacity (T-AOC); and reduced the hepatic expression of immunoglobulin M (IgM), transforming growth factor-beta (TGF-β) and glutathione-S-transferase (GST) genes versus the control diet. The addition of TPs at 50 or 200 mg/kg both ameliorated the HFD-induced increase in lipid droplets in the liver (50 mg/kg TP from 40.83% to 17.27%; 200 mg/kg TP to 25.33%), and increased the cumulative survival rate of the tilapia. The addition of 50 mg/kg TP had a marked effect increasing cumulative survival to 90%, and increasing the activities of serum acid phosphatase (ACP), T-AOC; and IgM, TGF-β, nuclear factor-κB (NF-κB), superoxide dismutase (SOD), and GST gene expression to the highest level of the HFD-fed groups. The 50 mg/kg TP-containing diet also significantly increased the hepatic expression of carnitine palmitoyltransferase 1 alpha (CPT1α) versus the control diet. In contrast, the tilapia fed an HFD supplemented with 200 mg/kg TPs had the lowest expression of adipose triglyceride lipase, hormone-sensitive lipase, CPT1α, fatty acid synthase and acetyl-CoA carboxylase alpha genes of any of the groups, which implies that the lower and higher levels of TP supplementation have differing effects on lipid metabolism. The 200 mg/kg supplement had lower cumulative survival rate (82%), and smaller effects on serum ACP and hepatic AKP activities than the 50 mg/kg dose, and had no significant effect on serum T-AOC or the expression of IgM, TGF-β, GST, or NF-κB genes in the tilapia. These results indicate that the beneficial effects of TPs on the lipid metabolism and health of fish fed an HFD are dose-related. Moreover, they are likely to be largely mediated through lipid catabolism.

Objective To identify the optimal factors in diffusion tensor imaging for predicting corticospinal tract (CST) injury caused by brain tumors. Materials and Methods This prospective study included 33 patients with motor weakness and 64 patients with normal motor function. The movement of the CST, minimum distance between the CST and the tumor, and relative fractional anisotropy (rFA) of the CST on diffusion tensor imaging, were compared between patients with motor weakness and normal function. Logistic regression analysis was used to obtain the optimal factor predicting motor weakness. Results In patients with motor weakness, the displacement (8.44 ± 6.64 mm) of the CST (p = 0.009), minimum distance (3.98 ± 7.49 mm) between the CST and tumor (p < 0.001), and rFA (0.83 ± 0.11) of the CST (p < 0.001) were significantly different from those of the normal group (4.64 ± 6.65 mm, 14.87 ± 12.04 mm, and 0.98 ± 0.05, respectively) (p = 0.009, p < 0.001, and p < 0.001). The frequencies of patients with the CST passing through the tumor (6%, p = 0.002), CST close to the tumor (23%, p < 0.001), CST close to a malignant tumor (high grade glioma, metastasis, or lymphoma) (19%, p < 0.001), and CST passing through infiltrating edema (19%, p < 0.001) in the motor weakness group, were significantly different from those of the patients with normal motor function (0, 8, 1, and 10%, respectively). Logistic regression analysis showed that decreased rFA and CST close to a malignant tumor were effective variables related to motor weakness. Conclusion Decreased fractional anisotropy, combined with closeness of a malignant tumor to the CST, is the optimal factor in predicting CST injury caused by a brain tumor.