Free fatty acids, not triglycerides, are associated with non-alcoholic liver injury progression in high fat diet induced obese rats

Abstract

BackgroundThe incidence of non-alcoholic fatty liver disease (NAFLD), commonly associated with obesity and metabolic syndrome, is increasing worldwide. However, the specific mechanisms that mediate the progression from simple steatosis to non-alcoholic steatohepatitis remain largely unclear. This study aimed to investigate the timedependent changes of triglyceride (TG) and free fatty acid (FFA) levels in the blood and liver over 24 weeks in high-fat diet-induced obese rats with NAFLD and to clarify the role of high FFA levels in the progression of liver injury.MethodsMale Wistar rats were randomly divided into three groups (n = 30 per group): the Control group, fed standard chow; the High-fat diet (HFD) group, fed high-fat chow; and the Acipimox group, fed an HFD plus acipimox (100 mg/kg/d, ig) for 8, 16 and 24 weeks. After treatment, blood and liver samples were collected for biochemical analyses, western blotting analysis and a histopathological study.ResultsThe visceral fat/weight and liver/body weight ratios were higher in both the HFD and Acipimox groups than in the Control group. The TG and FFA concentrations in blood and liver were increased in the HFD group and associated with elevated serum alanine aminotransferase (ALT) and liver malondialdehyde (MDA) levels and macro/microvesicular steatosis on hepatic fragments. Although the TG levels in the liver were similar between the HFD and Acipimox groups (p > 0.05), the FFA concentrations in the blood and liver were much lower in the latter group (p < 0.05). The Acipimox group showed normal ALT and MDA levels as well as less severe hepatic histological changes than did the HFD group (NAFLD activity score: 2.14 ± 0.14, 2.43 ± 0.20 and 2.63 ± 0.26 at 8, 16 and 24 weeks, respectively; p < 0.05 versus the HFD group at 24 weeks). The diacylglycerol acyltransferase 2 (DGAT2) protein levels were similar between the HFD and Acipimox groups (p > 0.05), but the protein expression level of carnitine palmitoyltransferase 1a (CPT-1a) was higher in the Acipimox group.ConclusionsLiver TG accumulation does not cause cellular injury in the liver; rather, FFAs or their metabolites are responsible for liver injury via increased oxidative stress. It is suggested that the therapeutic efforts to prevent non-alcoholic liver injury progression should be focused on reducing the burden of fatty acids transported to the liver or those being synthesized in the liver.

Saturated high-fat diet-induced obesity increases adenylate cyclase of myocardial β -adrenergic system and does not compromise cardiac function

“…; Liu et al. ). Furthermore, the obesity led to several comorbidities such as hypertension, dyslipidemia, glucose intolerance, insulin resistance, hyperinsulinemia, and hyperleptinemia; these findings are consistent with other researches (Dobrian et al.…”

Pathogenesis of Nonalcoholic Steatohepatitis: Interactions between Liver Parenchymal and Nonparenchymal Cells

“…Instead, hepatocyte triglyceride accumulation may act as a protective mechanism to counter FFA-induced lipotoxicity [40]. However, once the threshold of lipid storage is exceeded, the excessive accumulation of FFA leads to production of toxic lipid metabolites, such as ceramides, diacylglycerols, lysophosphatidylcholine, and oxidized cholesterol metabolites [20, 41]. These toxic lipid metabolites promote the overproduction of reactive oxygen species (ROS), which cause liver injury.…”

Long TE PRESS and STEAM for measuring the triglyceride glycerol CH2 protons at 3 T

“…The utility of the 4–4.5 ppm triglyceride glycerol methylene protons in fat composition assessment, for example in the study of osteoporosis, is emerging. In addition, there is potential for the resonance to provide information on free fatty acid to triglyceride content, which has shown relevance in disease . Short TE MRS techniques can be employed to measure the CH 2 glycerol resonances; however, the signal is overlapped by that from water.…”

“…Furthermore, we utilize the long TE sequences to assess the feasibility of using the glycerol methylene signal normalized to that of the methyl protons to estimate relative levels of triglyceride to free fatty acid content, a measure that has potential relevance in the study of disease. For example, levels of free fatty acids and triglycerides have been shown to become altered in rat models of non‐alcoholic fatty liver disease …”