Cholesterol and Lipoprotein Dynamics in a Hibernating Mammal

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces hepatic steatosis mediated by the aryl hydrocarbon receptor. To further characterize TCDD-elicited hepatic lipid accumulation, mice were gavaged with TCDD every 4 days for 28 days. Liver samples were examined using untargeted lipidomics with structural confirmation of lipid species by targeted high-resolution MS/MS, and data were integrated with complementary RNA-Seq analyses. Approximately 936 unique spectral features were detected, of which 379 were confirmed as unique lipid species. Both male and female samples exhibited similar qualitative changes (lipid species) but differed in quantitative changes. A shift to higher mass lipid species was observed, indicative of increased free fatty acid (FFA) packaging. For example, of the 13 lipid classes examined, triglycerides increased from 46 to 48% of total lipids to 68−83% in TCDD treated animals. Hepatic cholesterol esters increased 11.3-fold in male mice with moieties consisting largely of dietary fatty acids (FAs) (i.e., linolenate, palmitate, and oleate). Phosphatidylserines, phosphatidylethanolamines, phosphatidic acids, and cardiolipins decreased 4.1-, 5.0-, 5.4- and 7.4-fold, respectively, while ceramides increased 6.6-fold. Accordingly, the integration of lipidomic data with differential gene expression associated with lipid metabolism suggests that in addition to the repression of de novo fatty acid synthesis and β-oxidation, TCDD also increased hepatic uptake and packaging of lipids, while inhibiting VLDL secretion, consistent with hepatic fat accumulation and the progression to steatohepatitis with fibrosis.

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“…Indeed, gWAT has been identified as the source of increased circulating cholesterol levels in hibernating animals. 71 …”

Section: Discussionmentioning

confidence: 99%

Lipidomic Evaluation of Aryl Hydrocarbon Receptor-Mediated Hepatic Steatosis in Male and Female Mice Elicited by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Nault

Fader

Lydic

et al. 2017

Chem. Res. Toxicol.

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“…9A-C) (45,57,82,97,100,193,236,310,322,323,421,444,567). While ketone levels are maintained through Phase II fasting, they tend to decline significantly with entrance into Phase III (Figs.…”

Section: Ketone Bodiesmentioning

confidence: 99%

“…10C), and northern elephant seal pups following respective fasts of 4, 6, 10, 30, and 49 days (41,420,465,491,552). In contrast, fasting increases plasma cholesterol in the raptor B. buteo (by 25% and reversed with feeding), the rabbit (by 330% after 1 month), and in mammalian hibernators that do not eat during winter (17,154,158,182,315,323,421,478,519,541,575). For hibernators, at least, the increase in plasma cholesterol during fasting appears to stem from the reduction in fecal output and bile production, as both are routes for cholesterol removal (421).…”

Section: Cholesterolmentioning

confidence: 99%

“…Expression of apolipoprotein A-I, the main protein of high-density lipoproteins (HDL) increases in hibernating ground squirrels in liver and intestine, the two organs that synthesize it (153,155,351). Cholesterol levels in both HDL and low-density lipopoprotein particles are greater in hibernators compared with active ground squirrels, and HDL particle size also increases during hibernation (421).…”

Section: Cholesterolmentioning

confidence: 99%

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Integrative Physiology of Fasting

Secor

Carey

2016

Comprehensive Physiology

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150

144

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Extended bouts of fasting are ingrained in the ecology of many organisms, characterizing aspects of reproduction, development, hibernation, estivation, migration, and infrequent feeding habits. The challenge of long fasting episodes is the need to maintain physiological homeostasis while relying solely on endogenous resources. To meet that challenge, animals utilize an integrated repertoire of behavioral, physiological, and biochemical responses that reduce metabolic rates, maintain tissue structure and function, and thus enhance survival. We have synthesized in this review the integrative physiological, morphological, and biochemical responses, and their stages, that characterize natural fasting bouts. Underlying the capacity to survive extended fasts are behaviors and mechanisms that reduce metabolic expenditure and shift the dependency to lipid utilization. Hormonal regulation and immune capacity are altered by fasting; hormones that trigger digestion, elevate metabolism, and support immune performance become depressed, whereas hormones that enhance the utilization of endogenous substrates are elevated. The negative energy budget that accompanies fasting leads to the loss of body mass as fat stores are depleted and tissues undergo atrophy (i.e., loss of mass). Absolute rates of body mass loss scale allometrically among vertebrates. Tissues and organs vary in the degree of atrophy and downregulation of function, depending on the degree to which they are used during the fast. Fasting affects the population dynamics and activities of the gut microbiota, an interplay that impacts the host's fasting biology. Fasting-induced gene expression programs underlie the broad spectrum of integrated physiological mechanisms responsible for an animal's ability to survive long episodes of natural fasting.

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“…Other animals, such as the Minke whale, can have such high serum triglycerides that the serum appears lipemic (35). Hibernating squirrels are known to increase their serum and liver triglyceride content during the summer and then use these lipid stores as their energy source during hibernation (36). Regardless, the fact that animals purposefully develop fatty liver, elevated triglycerides and visceral fat stores is reminiscent of features observed in patients with metabolic syndrome.…”

Section: Classical Sites Of Fat Storagementioning

confidence: 99%

Redefining metabolic syndrome as a fat storage condition based on studies of comparative physiology

Johnson

Stenvinkel

Martin

et al. 2013

Obesity

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The metabolic syndrome refers to a constellation of signs including abdominal obesity, elevated serum triglycerides, low HDL-cholesterol, elevated blood pressure and insulin resistance. Today approximately one third of the adult population has the metabolic syndrome. While there is little doubt that the signs constituting the metabolic syndrome frequently cluster, much controversy exists over the definition, pathogenesis, or clinical utility. Here we present evidence from the field of comparative physiology that the metabolic syndrome is similar to the biological process that animals engage to store fat in preparation for periods of food shortage. We propose that the metabolic syndrome be changed to fat storage condition to more clearly align with its etiology. Obesity in humans is likely the consequences of both genetic predisposition (driven in part by thrifty genes) and environment. Recent studies suggest that the loss of the uricase gene may be one factor that predisposes humans to obesity today. Understanding the process animals engage to switch from a lean insulin-sensitive to an obese insulin-resistant state may provide novel insights into the cause of obesity and diabetes in humans, and unique opportunities for reversing their pathology.

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Cholesterol and Lipoprotein Dynamics in a Hibernating Mammal

Cited by 39 publications

References 62 publications

Lipidomic Evaluation of Aryl Hydrocarbon Receptor-Mediated Hepatic Steatosis in Male and Female Mice Elicited by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Lipidomic Evaluation of Aryl Hydrocarbon Receptor-Mediated Hepatic Steatosis in Male and Female Mice Elicited by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Integrative Physiology of Fasting

Redefining metabolic syndrome as a fat storage condition based on studies of comparative physiology

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