Excessive dietary fat intake induces lipid deposition and contributes to the progress of nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanisms are still unclear. Yellow catfish were given two experimental diets with dietary lipid levels of 11.3 and 15.4%, respectively, for 56 days, and the contents of triglyceride (TG), nonesterified free fatty acids (NEFA) and bile acid (BA), RNA-seq, enzymatic activities and mRNA expression were deteremined in the liver tissues. Hepatocytes from yellow catfish liver tissues were isolated and cultured. Fatty acids (FA) (palmitic acid: OA, oleic acid =1:1), pathway inhibitors (MA, autophagy inhibitor; guggulsterone, FXR inhibitor) and agonist (rapamyicn, autophagy agonist; GW4064, FXR agonist) were used to incubate the cells. TG and NEFA contents, ultrastructural observation, autophagic vesicles and intracellular LD,apoptosis,western blot and Co-IP, and Immunofluorescence analysis, enzymatic activities and Q-PCR were decided. Using RNA sequencing, we found that high fat diets induced changes in expression of many genes associated with the pathways of lipid metabolism and autophagy. The mRNA profiles of the differentially expressed genes (DEG) indicated that high dietary fat-induced lipid deposition was predominantly influenced by the inhibition of autophagy. Using primary hepatocytes, we found that fatty acids (FA) suppressed autophagy, which in turn reduced cellular free FA level by decreasing triglyceride (TG) breakdown. Moreover, our study indicated that farnesoid X receptor (FXR)-cyclic AMP-responsive element-binding protein (CREB) axis was the pivotal physiological switch regulating FA-induced changes of autophagy and lipid metabolism, which represented cellular defenses against FA-induced lipotoxicity. This discovery may provide new targets for treating pathological changes involved in the dysfunction of autophagy and metabolism, including NAFLD.

中文翻译：

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FXR介导的自噬抑制作用有助于FA诱导的TG积累，从而降低FA诱导的脂毒性。

饮食中脂肪摄入过多会导致脂质沉积，并导致非酒精性脂肪肝疾病（NAFLD）的进展。但是，其潜在机制仍不清楚。黄鱼接受了两种实验性饮食，分别在56天内的饮食脂质水平分别为11.3和15.4％，甘油三酸酯（TG），非酯化游离脂肪酸（NEFA）和胆汁酸（BA）的含量，RNA序列，确定肝脏组织中的酶活性和mRNA表达。分离并培养了来自黄色cat鱼肝脏组织的肝细胞。使用脂肪酸（FA）（棕榈酸：OA，油酸= 1：1），途径抑制剂（MA，自噬抑制剂，古古甾酮，FXR抑制剂）和激动剂（rapamyicn，自噬激动剂； GW4064，FXR激动剂）孵育细胞。TG和NEFA含量，超微结构观察，确定了自噬囊泡和细胞内LD，细胞凋亡，western blot和Co-IP，并进行了免疫荧光分析，酶活性和Q-PCR。使用RNA测序，我们发现高脂饮食诱导了许多与脂质代谢和自噬途径相关的基因表达的变化。差异表达基因（DEG）的mRNA图谱表明，高饮食脂肪诱导的脂质沉积主要受到自噬抑制的影响。使用原代肝细胞，我们发现脂肪酸（FA）抑制了自噬，进而通过减少甘油三酸酯（TG）的分解降低了细胞的游离FA水平。此外，我们的研究表明，法尼醇X受体（FXR）-环AMP响应元件结合蛋白（CREB）轴是调节FA诱导的自噬和脂质代谢变化的关键生理开关，它代表了针对FA诱导的脂毒性的细胞防御。这一发现可能为治疗与自噬和代谢功能障碍有关的病理变化提供新的靶点，包括NAFLD。