Hepatic energy metabolism in human diabetes mellitus, obesity and non-alcoholic fatty liver disease

Koliaki, Chrysi; Roden, Michael

doi:10.1016/j.mce.2013.06.002

Cited by 115 publications

(89 citation statements)

References 65 publications

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“…This implies that, when we analyse the effect of treatment as a dichotomous variable (improvement vs no improvement in fibrosis), there is no significant difference between arms (4/16 patients with improved fibrosis stage following ezetimibe compared with 1/12 in controls, p=0.136 with χ 2 test). While the impact on liver fibrosis needs further confirmation in larger studies, given the small number of patients included, the findings of this trial corroborate recent results from experimental models, suggesting that hepatic accumulation of non-triacylglycerol toxic lipid species (non-esterified cholesterol, saturated fatty acids, ceramides and diacylglycerols) triggers endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress, promoting liver injury, steatohepatitis and fibrosis [5,[7][8][9][10]. Several putative mechanisms linking cholesterol accumulation to hepatic stellate cell (HSC) activation and fibrogenesis have been demonstrated experimentally and reviewed elsewhere [5], including enhanced toll-like receptor (TLR)-4 pathway activation, which sensitises HSCs to the key fibrogenic factor transforming growth factor (TGF)-β1 [10], and reduces AMP-activated protein kinase-α (AMPK) activation [11] ( Fig.…”

Section: Ezetimibe Treatment Was Associated With An Increase Insupporting

confidence: 81%

Ezetimibe in the balance: can cholesterol-lowering drugs alone be an effective therapy for NAFLD?

Musso

2014

Diabetologia

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Section: Ezetimibe Treatment Was Associated With An Increase Insupporting

confidence: 81%

Ezetimibe in the balance: can cholesterol-lowering drugs alone be an effective therapy for NAFLD?

Musso

2014

Diabetologia

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“…Under conditions of abundant substrate availability (e.g., hepatic lipid accumulation), this uncoupling allows for continued oxidation of fatty acids beyond that required to meet cellular energy requirements (Chavin et al 1999). In fact, despite increased TCA cycle activity, hepatic ATP depletion is a consistent finding in hepatic steatosis (Chavin et al 1999, Koliaki & Roden 2013, Patterson et al 2016. In fatty liver disease, hepatic lipid accumulation, hyperglucagonemia and hypercortisolemia synergistically increase PPARa activity and upregulate gluconeogenic, beta-oxidative and ketogenic gene expression.…”

Section: Hepatic Lipids As Signaling Moleculesmentioning

confidence: 98%

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Geisler

Renquist

2017

Journal of Endocrinology

155

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Fatty liver can be diet, endocrine, drug, virus or genetically induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator-activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic and ketogenic genes, promoting hyperglycemia, hyperlipidemia and ketosis. The typical hormonal environment in fatty liver disease consists of hyperinsulinemia, hyperglucagonemia, hypercortisolemia, growth hormone deficiency and elevated sympathetic tone. These endocrine and metabolic changes further encourage hepatic steatosis by regulating adipose tissue lipolysis, liver lipid uptake, de novo lipogenesis (DNL), beta-oxidation, ketogenesis and lipid export. Hepatic lipid accumulation may be induced by 4 separate mechanisms: (1) increased hepatic uptake of circulating fatty acids, (2) increased hepatic de novo fatty acid synthesis, (3) decreased hepatic beta-oxidation and (4) decreased hepatic lipid export. This review will discuss the hormonal regulation of each mechanism comparing multiple physiological models of hepatic lipid accumulation. Nonalcoholic fatty liver disease (NAFLD) is typified by increased hepatic lipid uptake, synthesis, oxidation and export. Chronic hepatic lipid signaling through PPARgamma results in gene expression changes that allow concurrent activity of DNL and beta-oxidation. The importance of hepatic steatosis in driving systemic metabolic dysfunction is highlighted by the common endocrine and metabolic disturbances across many conditions that result in fatty liver. Understanding the mechanisms underlying the metabolic dysfunction that develops as a consequence of hepatic lipid accumulation is critical to identifying points of intervention in this increasingly prevalent disease state.

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“…According to current paradigms, chronic insulin resistance is the common feature of these diseases (3,4) and relates to intracellular concentrations of triglycerides (TG) and lipotoxins (5). There is evidence that a chronic high-fat diet in mice and humans leads to insulin resistance via similar mechanisms (6,7).…”

Section: Introductionmentioning

confidence: 99%

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

Hernández¹,

Kahl²,

Seelig³

et al. 2017

Journal of Clinical Investigation

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159

130

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H and ex vivo2 H magnetic resonance spectroscopy before and during hyperinsulinemiceuglycemic clamps with isotope dilution. Mice underwent identical clamp procedures and hepatic transcriptome analyses.RESULTS. PO administration decreased whole-body, hepatic, and adipose tissue insulin sensitivity by 25%, 15%, and 34%, respectively. Hepatic triglyceride and ATP content rose by 35% and 16%, respectively. Hepatic gluconeogenesis increased by 70%, and net glycogenolysis declined by 20%. Mouse transcriptomics revealed that PO differentially regulates predicted upstream regulators and pathways, including LPS, members of the TLR and PPAR families, NF-κB, and TNF-related weak inducer of apoptosis (TWEAK). CONCLUSION.Saturated fat ingestion rapidly increases hepatic lipid storage, energy metabolism, and insulin resistance. This is accompanied by regulation of hepatic gene expression and signaling that may contribute to development of NAFLD. PO results in increased circulating TG, glucagon, and incretins. After PO administration, TG in plasma rose by 59% (area under the time curve [AUC], P < 0.001) and by 156% in chylomicrons (AUC, P = 0.009) (Figure 2A). The AUC for plasma free fatty acids (FFA) ( Figure 2B) and insulin concentrations ( Figure 2C) was unchanged, while the AUC for plasma C-peptide was 28% higher after PO ingestion versus VCL (P < 0.005, Figure 2D). Of note, FFA were increased at 300, 420, and 480 minutes. Blood glucose levels were not different between PO-and VCL-treated groups ( Figure 2E). Plasma glucagon rose by 41% (AUC, P < 0.0001) only after PO ingestion ( Figure 2F). Also, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels were markedly increased and remained elevated after PO ingestion (both P < 0.005) (Supplemental Figure 2; supplemental material available online with this article; https://doi.org/10.1172/ JCI89444DS1). Circulating levels of TNF-α, IL-6, fetuin-A, chemerin, omentin, and cortisol were not different between PO and VCL groups (P > 0.5 for all) (Supplemental Table 1). REGISTRATION. The Journal of Clinical Investigation C L I N I C A L M E D I C I N EPO induces insulin resistance at whole-body, liver, and adipose tissue levels. Insulin sensitivity was measured using hyperinsulinemic-euglycemic clamp tests in healthy humans. Steady state was reached (Supplemental Figure 1), and pertinent parameters were analyzed during this time. PO ingestion reduced WBIS by 25% compared with VCL treatment (P = 0.0005, Figure 3A). Furthermore, after PO, volunteers also showed a decrease of 22% (P = 0.002) in the rate of glucose disappearance (Rd), mostly due to a 33% (P = 0.01) reduction in glucose oxidation (GOX), while the rate of nonoxidative glucose disposal remained unchanged

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Hepatic energy metabolism in human diabetes mellitus, obesity and non-alcoholic fatty liver disease

Cited by 115 publications

References 65 publications

Ezetimibe in the balance: can cholesterol-lowering drugs alone be an effective therapy for NAFLD?

Ezetimibe in the balance: can cholesterol-lowering drugs alone be an effective therapy for NAFLD?

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

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