In a Prediabetic Model, Empagliflozin Improves Hepatic Lipid Metabolism Independently of Obesity and before Onset of Hyperglycemia

Abstract

Recent studies suggest that treatment with SGLT-2 inhibitors can reduce hepatic lipid storage and ameliorate non-alcoholic fatty liver disease (NAFLD) development beyond their glycemic benefits. However, the exact mechanism involved is still unclear. We investigated the hepatic metabolic effect of empagliflozin (10 mg/kg/day for eight weeks) on the development of NAFLD and its complications using HHTg rats as a non-obese prediabetic rat model. Empagliflozin treatment reduced neutral triacylglycerols and lipotoxic diacylglycerols in the liver and was accompanied by significant changes in relative mRNA expression of lipogenic enzymes (Scd-1, Fas) and transcription factors (Srebp1, Pparγ). In addition, alterations in the gene expression of cytochrome P450 proteins, particularly Cyp2e1 and Cyp4a, together with increased Nrf2, contributed to the improvement of hepatic lipid metabolism after empagliflozin administration. Decreased circulating levels of fetuin-A improved lipid metabolism and attenuated insulin resistance in the liver and in peripheral tissues. Our results highlight the beneficial effect of empagliflozin on hepatic lipid metabolism and lipid accumulation independent of obesity, with the mechanisms understood to involve decreased lipogenesis, alterations in cytochrome P450 proteins, and decreased fetuin-A. These changes help to alleviate NAFLD symptoms in the early phase of the disease and before the onset of diabetes.

Beneficial Effects of Empagliflozin Are Mediated by Reduced Renal Inflammation and Oxidative Stress in Spontaneously Hypertensive Rats Expressing Human C-Reactive Protein

“…Thus, the absence of an empagliflozin effect on the reduction of albuminuria in adult rats could be explained either by the existing long-term changes in the kidneys of ageing animals or by the higher susceptibility of young animals to pharmacological interventions [ 26 ]. Similarly, our previous study performed in another non-diabetic hypertensive model—adult Ren-2 transgenic rats—did not show any effect of empagliflozin on proteinuria or albuminuria [ 17 ]; while a reduction of albuminuria was disclosed in a pre-diabetic rat model—hereditary hypertriglyceridemic rats [ 18 ]. Conversely, a reduction of albuminuria in young rats was associated with substantial attenuation of several parameters of oxidative stress (reduced levels of lipoperoxidation products TBARS and conjugated dienes, increased activity of glutathione peroxidase, increased glutathione levels, etc.)…”

“…Conversely, the effects of empagliflozin treatment on gene expression of other pro-inflammatory cytokines TGF-β, TNF-α were not demonstrated. However, we and others found ambiguous effects of gliflozins therapy on distinct pro-inflammatory markers in non-diabetic rat strains—sometimes affecting more TNF-α [ 17 ], MCP-1 [ 18 ], or IL-1β and NF-κB [ 18 ]. Moreover, it could not be excluded that only those pro-inflammatory parameters which were upregulated by the insertion of the CRP transgene (IL-6, but not TNF-α) [ 19 ], could be influenced by empagliflozin therapy.…”

“…The beneficial effects of gliflozins on renal function were observed in spontaneously hypertensive rats with heart failure [ 15 ] and also partly in rats after 5/6 nephrectomy [ 16 ]. Our studies in non-diabetic models, namely in hypertensive Ren-2 transgenic rats (TGR) [ 17 ], a model of angiotensin II-dependent hypertension, as well as in a model of metabolic syndrome and prediabetes—hereditary hypertriglyceridemic rats (HHTG) [ 18 ], showed the beneficial effects of empagliflozin treatment without a glucose-lowering effect. In these models, SGLT-2 inhibition led to a reduction in body weight and visceral adiposity, a decrease of insulin and leptin levels, and an improvement of hepatic metabolism, as well as the attenuation of oxidative stress and inflammation.…”

Empagliflozin Ameliorates Progression From Prediabetes to Diabetes and Improves Hepatic Lipid Metabolism: A Systematic Review

“…It has also reduced the mRNA expression of fatty acid synthetase (fas) and stearoyl-CoA desaturase 1 (scd1), which are lipogenic enzymes. EMPA treatment reduces the expression of sterol regulatory element-binding protein 1 (srebp1) and peroxisome proliferator-activated receptor-α (PPAR-α), and thus, it decreases the hepatic lipid accumulation by suppressing hepatic lipogenesis [ 11 ]. Scd1 is found to be decreased in other studies as well [ 7 , 37 ].…”

Innovative Molecular Target and Therapeutic Approaches in Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH) 2.0

“…Indeed, in several trials, these compounds appear to reduce liver fat content, AST/ALT levels, and even liver stiffness, suggesting they may be effective in future NAFLD-specific treatment protocols [ 13 ]. In particular, the treatment with empagliflozin, an SGLT-2 inhibitor, not only decreases hepatic lipid accumulation in diet-induced NAFLD [ 14 ] but in prediabetic rats, it mitigates hepatic steatosis and modulates the expression of genes involved in lipogenesis and lipid storage [ 15 ].…”