Role of Choline Deficiency in the Fatty Liver Phenotype of Mice Fed a Low Protein, Very Low Carbohydrate Ketogenic Diet

Schugar, Rebecca C.; Huang, Xiaojing; Moll, Ashley R.; Brunt, Elizabeth M.; Crawford, Peter A.

doi:10.1371/journal.pone.0074806

Cited by 43 publications

(38 citation statements)

References 65 publications

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“…This is in line with metabolic changes observed in previous studies in mice (2,16,20,22) and may indicate an early stage of nonalcoholic fatty liver disease (16,36). Recent short-term studies have shown that supplementation of KD with choline or methionine could limit hepatic steatosis and the proinflammatory state of the liver, respectively (31,37). However, the similar methionine and higher choline content of KD in our study did not prevent signs of steatohepatitis in the long term.…”

Section: Discussionsupporting

confidence: 91%

Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice

Ellenbroek

Dijck

Töns

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

126

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Ellenbroek JH, van Dijck L, Töns HA, Rabelink TJ, Carlotti F, Ballieux BE, de Koning EJ. Long-term ketogenic diet causes glucose intolerance and reduced ␤-and ␣-cell mass but no weight loss in mice. Am J Physiol Endocrinol Metab 306: E552-E558, 2014. First published January 7, 2014 doi:10.1152/ajpendo.00453.2013.-High-fat, low-carbohydrate ketogenic diets (KD) are used for weight loss and for treatment of refractory epilepsy. Recently, short-time studies in rodents have shown that, besides their beneficial effect on body weight, KD lead to glucose intolerance and insulin resistance. However, the long-term effects on pancreatic endocrine cells are unknown. In this study we investigate the effects of long-term KD on glucose tolerance and ␤-and ␣-cell mass in mice. Despite an initial weight loss, KD did not result in weight loss after 22 wk. Plasma markers associated with dyslipidemia and inflammation (cholesterol, triglycerides, leptin, monocyte chemotactic protein-1, IL-1␤, and IL-6) were increased, and KD-fed mice showed signs of hepatic steatosis after 22 wk of diet. Long-term KD resulted in glucose intolerance that was associated with insufficient insulin secretion from ␤-cells. After 22 wk, insulin-stimulated glucose uptake was reduced. A reduction in ␤-cell mass was observed in KD-fed mice together with an increased number of smaller islets. Also ␣-cell mass was markedly decreased, resulting in a lower ␣-to ␤-cell ratio. Our data show that long-term KD causes dyslipidemia, a proinflammatory state, signs of hepatic steatosis, glucose intolerance, and a reduction in ␤-and ␣-cell mass, but no weight loss. This indicates that long-term high-fat, lowcarbohydrate KD lead to features that are also associated with the metabolic syndrome and an increased risk for type 2 diabetes in humans. pancreatic islet; ketogenic diet; glucose intolerance; ␤-cell; ␣-cell

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Section: Discussionsupporting

confidence: 91%

Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice

Ellenbroek

Dijck

Töns

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

126

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“…3I-M), as high cholesterol levels are a concern with a high-fat diet (31). Reports of mice fed the Bioserv-KD describe increases in hepatic triglycerides and fat accumulation, together with a reduction in body weight, due to choline deficiency combined with low-protein and high-fat content (32). In line with these findings, animals fed the Bioserv-KD showed a significant increase in cholesterol (Fig.…”

Section: The Shflc Diet Is Safe and Nutritionally Completesupporting

confidence: 67%

A Supplemented High-Fat Low-Carbohydrate Diet for the Treatment of Glioblastoma

Martuscello

Vedam‐Mai

McCarthy

et al. 2016

Clinical Cancer Research

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Purpose: Dysregulated energetics coupled with uncontrolled proliferation has become a hallmark of cancer, leading to increased interest in metabolic therapies. Glioblastoma (GB) is highly malignant, very metabolically active, and typically resistant to current therapies. Dietary treatment options based on glucose deprivation have been explored using a restrictive ketogenic diet (KD), with positive anticancer reports. However, negative side effects and a lack of palatability make the KD difficult to implement in an adult population. Hence, we developed a less stringent, supplemented high-fat low-carbohydrate (sHFLC) diet that mimics the metabolic and antitumor effects of the KD, maintains a stable nutritional profile, and presents an alternative clinical option for diverse patient populations. Experimental Design: The dietary paradigm was tested in vitro and in vivo, utilizing multiple patient-derived gliomasphere lines. Cellular proliferation, clonogenic frequency, and tumor stem cell population effects were determined in vitro using the neurosphere assay (NSA). Antitumor efficacy was tested in vivo in preclinical xenograft models and mechanistic regulation via the mTOR pathway was explored. Results: Reducing glucose in vitro to physiologic levels, coupled with ketone supplementation, inhibits proliferation of GB cells and reduces tumor stem cell expansion. In vivo, while maintaining animal health, the sHFLC diet significantly reduces the growth of tumor cells in a subcutaneous model of tumor progression and increases survival in an orthotopic xenograft model. Dietary-mediated anticancer effects correlate with the reduction of mTOR effector expression. Conclusions: We demonstrate that the sHFLC diet is a viable treatment alternative to the KD, and should be considered for clinical testing. Clin Cancer Res; 22(10); 2482–95. ©2015 AACR.

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“…Mitochondrial isolation and respiration. Mitochondrial isolation and respiration studies were conducted and assessed as described previously (79,85).…”

Section: Methodsmentioning

confidence: 99%

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

et al. 2014

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R e s e a R c h a R t i c l e5 1Ketogenic insufficiency causes hepatic inflammation, injury, and altered glucose metabolism in the setting of carbohydrate-replete overnutrition. To determine the effects of ketogenic insufficiency in the context of overnutrition, mice previously receiving ASOs for 2 weeks while on a standard low-fat chow diet were then maintained for 8 weeks on a 60% high-fat diet (HFD) commonly used to induce hyperglycemia, hepatic steatosis, and inflammation in WT mice. HMGCS2 immunoblots indicated that hepatic HMGCS2 mice (Supplemental Figure 2, A-C). HMGCS2 ASO-treated mice also exhibited normal serum free fatty acid (FFA) and TAG concentrations and a normal physiologic distribution of residual βOHB and AcAc (Supplemental Figure 2, D-F). Interestingly, HMGCS2 ASO-treated mice displayed mild, but very consistently elevated, blood glucose concentrations (160.9 ± 3.2 mg/dl vs. 145.0 ± 3.4 mg/dl in controls, n = 28-36/group, P = 0.0013), without changes in serum insulin concentrations (Supplemental Figure 2, G and H). C]pyruvate, quantified by NMR profiling of perfused liver extracts from ASO-treated mice fed a 60% HFD for 8 weeks. n = 4-5/group. *P < 0.05, **P < 0.01, ***P < 0.001 by Student's t test.

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Role of Choline Deficiency in the Fatty Liver Phenotype of Mice Fed a Low Protein, Very Low Carbohydrate Ketogenic Diet

Cited by 43 publications

References 65 publications

Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice

Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice

A Supplemented High-Fat Low-Carbohydrate Diet for the Treatment of Glioblastoma

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

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