Partial MCT1 invalidation protects against diet-induced non-alcoholic fatty liver disease and the associated brain dysfunction

Hadjihambi, Anna; Konstantinou, Christos; Klohs, Jan; Monsorno, Katia; Guennec, Adrien Le; Donnelly, Chris; Cox, I. Jane; Kusumbe, Anjali P.; Hosford, Patrick S.; Soffientini, Ugo; Lecca, Salvatore; Mameli, Manuel; Jalan, Rajiv; Paolicelli, Rosa Chiara; Pellerin, Luc

doi:10.1016/j.jhep.2022.08.008

Cited by 36 publications

(16 citation statements)

References 41 publications

(33 reference statements)

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“…We cannot discard the possibility that these differences were due to the duration of the study or diet composition. In this regard, previous work has shown an amelioration of NAFLD following inhibition of microglia [ 104 , 105 ].…”

Section: Discussionmentioning

confidence: 99%

Olive- and Coconut-Oil-Enriched Diets Decreased Secondary Bile Acids and Regulated Metabolic and Transcriptomic Markers of Brain Injury in the Frontal Cortexes of NAFLD Pigs

et al. 2022

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The objective of this study was to investigate the effect of dietary fatty acid (FA) saturation and carbon chain length on brain bile acid (BA) metabolism and neuronal number in a pig model of pediatric NAFLD. Thirty 20-day-old Iberian pigs, pair-housed in pens, were randomly assigned to receive one of three hypercaloric diets for 10 weeks: (1) lard-enriched (LAR; n = 5 pens), (2) olive-oil-enriched (OLI, n = 5), and (3) coconut-oil-enriched (COC; n = 5). Pig behavior and activity were analyzed throughout the study. All animals were euthanized on week 10 and frontal cortex (FC) samples were collected for immunohistochemistry, metabolomic, and transcriptomic analyses. Data were analyzed by multivariate and univariate statistics. No differences were observed in relative brain weight, neuronal number, or cognitive functioning between diets. Pig activity and FC levels of neuroprotective secondary BAs and betaine decreased in the COC and OLI groups compared with LAR, and paralleled the severity of NAFLD. In addition, OLI-fed pigs showed downregulation of genes involved in neurotransmission, synaptic transmission, and nervous tissue development. Similarly, COC-fed pigs showed upregulation of neurogenesis and myelin repair genes, which caused the accumulation of medium-chain acylcarnitines in brain tissue. In conclusion, our results indicate that secondary BA levels in the FCs of NAFLD pigs are affected by dietary FA composition and are associated with metabolic and transcriptomic markers of brain injury. Dietary interventions that aim to replace saturated FAs by medium-chain or monounsaturated FAs in high-fat hypercaloric diets may have a negative effect on brain health in NAFLD patients.

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Section: Discussionmentioning

confidence: 99%

Olive- and Coconut-Oil-Enriched Diets Decreased Secondary Bile Acids and Regulated Metabolic and Transcriptomic Markers of Brain Injury in the Frontal Cortexes of NAFLD Pigs

et al. 2022

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“…Not only advanced chronic liver diseases but even pre-cirrhotic stages of NAFLD can be associated with brain dysfunction and cognitive decline. Moreover, NAFLD is correlated with lowgrade brain tissue inflammation and hypoxia in the presence of overweight/obesity, along with metabolic, cerebrovascular, and behavioral changes, suggesting the early stage of overweight/obesity-related encephalopathy [33].…”

Section: Discussionmentioning

confidence: 99%

Overweight/Obesity Increases the Risk of Overt Hepatic Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt in Cirrhotic Patients

Yin

Cheng

et al. 2023

JPM

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The purpose of this study was to investigate the effect of body mass index (BMI) on the prevalence of overt hepatic encephalopathy (OHE) after the transjugular intrahepatic portosystemic shunt (TIPS) procedure in decompensated cirrhotic patients. A retrospective observational cohort study of 145 cirrhotic patients receiving TIPS was carried out in our department from 2017 to 2020. The relationships between BMI and clinical outcomes including OHE, as well as risk factors of developing post-TIPS OHE, were analyzed. BMI was categorized as normal weight (18.5 ≤ BMI < 23.0 kg/m2), underweight (BMI < 18.5 kg/m2), and overweight/obese (BMI ≥ 23.0 kg/m2). Among the 145 patients, 52 (35.9%) were overweight/obese and 50 (34%) had post-TIPS OHE. Overweight/obese patients more frequently had OHE compared with normal weight patients (OR: 2.754, 95% CI: 1.236–6.140; p = 0.013). Overweight/obesity (p = 0.013) and older age (p = 0.030) were independent risk factors for post-TIPS OHE according to the logistic regression analysis. Kaplan–Meier curve analysis suggested that overweight/obese patients had the highest cumulative incidence of OHE (log-rank p = 0.0118). In conclusion, overweight/obesity and older age may raise the risk of post-TIPS OHE in cirrhotic patients.

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“…[ 10 a] Lactate transporter MCT1 +/+ mice with NAFLD present higher mitochondrial respiratory capacities and exhibit inflammation‐associated characteristics in microglia and astrocytes, whereas not in MCT1 +/− animals. [ 16 ] As NAFLD could drive liver cancer carcinogenesis, the lactate‐associated metabolic signatures of liver inflammation are similar to tumors and offer potential diagnostic value.…”

Section: Lactate Is a Promoter Of Malignancymentioning

confidence: 99%

Recent Progress in the Therapeutic Modulation of Lactate for Cancer Treatment

Zhao

Luo

et al. 2022

Advanced Therapeutics

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Lactate is the end-product of glycolysis activity, which is universally upregulated in most solid tumor indications. Increasing evidence shows that lactate is also involved in various tumor-related events, presenting indispensable roles for supporting tumor growth, progression, and invasion. Typically, lactate in the tumor microenvironment (TME) can not only be exploited as an energy source for sustaining cancer cell survival but also function as a messenger modulator for signal transduction via receptor or non-receptor pathways for cell communications therein. In addition, the presence of lactate substantially suppresses anti-tumor immunity and mediates the epigenetic upregulation of key oncogenes via lysine lactylation of histone. In this review, a concise yet comprehensive summary on recent studies regarding the myriad roles and functions of lactate on tumor cells and TME is provided, based on which there is further discussion of the emerging antitumor strategies targeting the lactate metabolism including its biosynthesis and transporting. This review may facilitate the development of more effective antitumor therapies. Aberrant Lactate Production in the Unique Metabolic Landscape of Tumor CellsThe glucose-dependent glycolysis activity is the major source of lactate in cellular environment, which is intricately regulated through the cooperation of multiple enzymes (Figure 1A). Although less efficient than oxidative phosphorylation in terms

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Partial MCT1 invalidation protects against diet-induced non-alcoholic fatty liver disease and the associated brain dysfunction

Cited by 36 publications

References 41 publications

Olive- and Coconut-Oil-Enriched Diets Decreased Secondary Bile Acids and Regulated Metabolic and Transcriptomic Markers of Brain Injury in the Frontal Cortexes of NAFLD Pigs

Olive- and Coconut-Oil-Enriched Diets Decreased Secondary Bile Acids and Regulated Metabolic and Transcriptomic Markers of Brain Injury in the Frontal Cortexes of NAFLD Pigs

Overweight/Obesity Increases the Risk of Overt Hepatic Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt in Cirrhotic Patients

Recent Progress in the Therapeutic Modulation of Lactate for Cancer Treatment

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