stress induced by defective PPAR␣ signaling in the pathogenesis of hepatic steatosis. Am J Physiol Endocrinol Metab 306: E1264 -E1273, 2014. First published April 15, 2014; doi:10.1152/ajpendo.00438.2013.-Emerging evidence demonstrates a close interplay between disturbances in mitochondrial function and ER homeostasis in the development of the metabolic syndrome. The present investigation sought to advance our understanding of the communication between mitochondrial dysfunction and ER stress in the onset of hepatic steatosis in male rodents with defective peroxisome proliferator-activated receptor-␣ (PPAR␣) signaling. Genetic depletion of PPAR␣ or perturbation of PPAR␣ signaling by high-fructose diet compromised the functional activity of metabolic enzymes involved in mitochondrial fatty acid ␤-oxidation and induced hepatic mitochondrial stress in rats and mice. Inhibition of PPAR␣ activity further enhanced the expression of apolipoprotein B (apoB) mRNA and protein, which was associated with reduced mRNA expression of the sarco/endoplasmic reticulum calcium ATPase (SERCA), the induction of hepatic ER stress, and hepatic steatosis. Restoration of PPAR␣ activity recovered the metabolic function of the mitochondria and ER, alleviated systemic hypertriglyceridemia, and improved hepatic steatosis. These findings unveil novel roles for PPAR␣ in mediating stress signals between hepatic subcellular stress-responding machinery and in the onset of hepatic steatosis under conditions of metabolic stress.peroxisome proliferator-activated receptor-␣; endoplasmic reticulum; mitochondrial and endoplasmic reticulum stress; apolipoprotein B; very-low density lipoprotein; hepatic steatosis PERTURBATIONS IN LIPID METABOLISM are involved in the pathogenesis of a cluster of chronic metabolic diseases, including fatty liver disease, insulin resistance, type 2 diabetes, and atherosclerosis. The peroxisome proliferator-activated receptor (PPAR) nuclear receptor family is a group of transcription factors that critically regulate signaling at the interface of lipid metabolism and inflammation (3). Among them, the isoform PPAR␣ is expressed predominantly in the liver, where it promotes fatty acid ␤-oxidation, ketogenesis, lipid transport, and gluconeogenesis (4, 26). The majority of the genes involved in mitochondrial fatty acid ␤-oxidation are transcriptionally regulated by PPAR␣. As energy-regulating metabolic machinery, mitochondria dynamically communicate with other subcellular organelles such as the endoplasmic reticulum (ER) (10). Mitochondrial dysfunction is a contributing factor to the onset of insulin resistance; impairment of mitochondrial function in human myocytes increases predisposition to intramyocellular lipid accumulation and insulin resistance (17,28).Research over the past decade has established a compelling connection between lipid-induced ER stress and the metabolic syndrome (18, 23). The onset of obesity and hepatic steatosis are usually accompanied by increased secretion of hepatic very-low-density lipoprotein-trigly...

T he human gastrointestinal tract is populated with at least 100 trillion bacteria that provide their host with dietary metabolites. Extensive studies have demonstrated that human gut microbiota affect energy balance, gut permeability, serum lipopolysaccharides levels, and metabolic inflammation associated with obesity and diabetes mellitus.1 Subjects with obesity and type 2 diabetes mellitus are characterized by altered gut microbiota, inflammation, and gut barrier disruption. In addition, the population of beneficial gut bacteria has been found to be reduced in animal models of metabolic syndrome. For instance, the abundance of a beneficial gut bacterium, Akkermansia muciniphila (A muciniphila), is significantly lower in the genetically obese ob/ob mice or mice fed a high-fat diet compared with their lean littermates. Increased colonization of A muciniphila has also been found to be capable of reversing high-fat diet-induced metabolic disorders.2 In contrast, disease-promoting gut bacteria induce metabolic disorders. For instance, a strain of the Enterobacter cloacae, B29, isolated from a morbidly obese human, induced obesity and insulin resistance in a rodent model, and the severity of disease was found to be closely related to the lipid content in the diet. 3A muciniphila is a mucin-degrading bacterium that resides in the mucus layer of intestine, and it abundantly colonizes in this nutrient-rich environment. 4 Oral administration of live A muciniphila has been shown to prevent diet-induced obesity by altering adipose tissue metabolism and gut permeability without affecting food intake.2 However, the regulatory effect of A muciniphila on host lipid metabolism, particularly on hepatic lipid signaling and lipoprotein metabolism, is unexplored.© 2016 American Heart Association, Inc. Objective-Akkermansia muciniphila (A muciniphila) is a mucin-degrading bacterium that resides in the mucus layer whose abundance inversely correlates with body weight and the development of diabetes mellitus in mice and humans. The objective of this study was to explore the regulatory effect of A muciniphila on host lipoprotein metabolism, insulin sensitivity, and hepatic metabolic inflammation. Approach and Results-By establishing a novel mouse model that colonized the A muciniphila in the gastrointestinal tract of the cAMP-responsive binding protein H (CREBH)-deficient mouse and in vivo chylomicron assay, we found that increased colonization of A muciniphila in the gastrointestinal tract of wild-type mice protected mice from an acute fat load-induced hyperlipidemia compared with vehicle-treated mice. A muciniphila administration also significantly ameliorated chronic hypertriglyceridemia, improved insulin sensitivity, and prevented overproduction of postprandial chylomicrons in CREBH-null mice. Mechanistic studies revealed that increased A muciniphila colonization induced expression of low-density lipoprotein receptors and apolipoprotein E in the hepatocytes of CREBH-null mice, which facilitated the uptake of intermediate-density...

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The activation of sterol regulatory element binding proteins (SREBPs) is regulated by insulin-induced genes-1 and -2 (Insig-1 and Insig-2) and SCAP. We previously reported that feeding R-α-lipoic acid (LA) to Zucker Diabetic Fatty (ZDF) rats improves severe hypertriglyceridemia. In this study, we investigated the role of cAMP-responsive element-binding protein H (CREBH) in the lipid-lowering mechanism of LA and its involvement in the SREBP-1c and Insig pathway. Incubation of McA cells with LA (0.2 mM) or glucose (6 mM) stimulated activation of CREBH. LA treatment further induced mRNA expression of Insig-1 and Insig-2a, but not Insig-2b, in glucose-treated cells. In vivo, feeding LA to obesity-induced hyperlipidemic ZDF rats activated hepatic CREBH and stimulated transcription and translation of Insig-1 and Insig-2a. Activation of CREBH and Insigs induced by LA suppressed processing of SREBP-1c precursor into nuclear SREBP-1c, which subsequently inhibited expression of genes involved in fatty acid synthesis, including FASN, ACC and SCD-1, and reduced triglyceride contents in both glucose-treated cells and ZDF rat livers. Additionally, LA treatment also decreased abundances of very-low-density lipoprotein (VLDL)-associated apolipoproteins, apoB100 and apoE, in glucose-treated cells and livers of ZDF rats, leading to decreased secretion of VLDL and improvement of hypertriglyceridemia. This study unveils a novel molecular mechanism whereby LA lowers triglyceride via activation of hepatic CREBH and increased expression of Insig-1 and Insig-2a to inhibit de novo lipogenesis and VLDL secretion. These findings provide novel insight into the therapeutic potential of LA as an anti–hypertriglyceridemia dietary molecule.