Decreased Fatty Acid <i>β</i>-Oxidation Is the Main Cause of Fatty Liver Induced by Polyunsaturated Fatty Acid Deficiency in Mice

Abstract

Insufficient intake of polyunsaturated fatty acids (PUFA) causes fatty liver. The mechanism responsible is primarily related to increased lipogenesis and decreased FA degradation based on rodent studies. However, these studies were limited by the fact that the typical PUFA-deficient diets contained insufficient amounts of long-chain FA, the PUFA-containing diets were primarily composed of n-3 PUFA-enriched oil, and the intake of PUFA was excessive compared with the physiological requirement. To address these issues, mice were fed a PUFA-deficient diet containing long-chain FA at a standard fed level and then were orally fed a n-3/n-6-balanced PUFA-containing oil [PUFA (+)] or a PUFA-deficient oil [PUFA (−)] at physiological relevant levels (0.1 mL/mouse/2d). We compared these groups and examined whether fatty liver in PUFA deficiency was attributable to both the effects of increased lipogenesis and decreased FA catabolism. Compared with the PUFA (+) group, the PUFA (−) group showed increases in liver triglyceride and serum FA content. Hepatic gene expression of several mitochondrial β-oxidation enzymes, the serum 3-hydroxybutyrate level, and DNA-binding ability of peroxisome proliferator-activated receptor α (PPARα) were increased in the PUFA (+) group, whereas these adaptive responses were significantly attenuated in the PUFA (−) group. The hepatic expression of typical lipogenesis genes did not differ between the groups. Therefore, fatty liver in PUFA deficiency is attributable to suppression of the FA-degrading system probably from decreased PPARα adaptive responsiveness, and PUFA may be an essential factor for PPARα functioning. This finding is helpful for managing clinical situations having a risk of PUFA deficiency.

PPARs as Metabolic Regulators in the Liver: Lessons from Liver-Specific PPAR-Null Mice

“…Polyunsaturated FAs (PUFAs) are endogenous activators of PPARα [5,6], and when mice are fed a high-fat diet (HFD) without PUFAs for 5 weeks, they show high serum FA levels and severe fatty liver. Supplementation of the HFD with PUFAs, mainly linoleic acid and α-linolenic acid, ameliorated fatty liver due to PPARα activation and enhanced hepatic FA β-oxidation [16].…”

Hepatocyte-Secreted Autotaxin Exacerbates Nonalcoholic Fatty Liver Disease Through Autocrine Inhibition of the PPARα/FGF21 Axis

“… 37 , 61 , 62 , 63 , 64 Mice with global and hepatocyte-specific PPARα are more susceptible to HFD-induced hepatic steatosis and methionine/choline-deficient diet–induced NASH, 65 while treatment with PPARα agonists ameliorates hepatic steatosis and inflammation in several different types of NAFLD mouse models. 66 , 67 However, clinical trials failed to show any therapeutic benefits of either PPARα agonists or a PPARα/δ agonist on liver histology in NASH patients despite significant improvements in circulating lipid profiles (NCT02704403), 68 suggesting that PPARα activation alone is insufficient for the treatment of NAFLD. In this connection, an augmented ATX–LPA axis has been linked to several pathophysiological pathways involved in NAFLD development, including exacerbation of proinflammatory responses, 69 induction of insulin resistance, 18 , 49 apoptosis, 70 and fibrosis 15 , 16 , 71 in different disease models.…”

Prevalence of Hepatic Steatosis Among Children and Adolescents With Cystic Fibrosis and Its Association With Nutritional Status

“…Although the etiopathogenesis in most patients is unknown, it has been associated with specific nutritional deficiencies, altered phospholipid metabolism, 8 and malnutrition 9 . Essential fatty acid deficiency has been described in patients with CF and pancreatic insufficiency, 10 while experimental studies with rats have linked this deficiency to HS 11 . According to the consensus body of hepatobiliary diseases related to CF, when patients without malnutrition present with steatosis, it is important to investigate the possibility of diabetes mellitus 12 .…”